Cosmetic compositions containing quinones and their topical use on skin and hair

ABSTRACT

Described are compositions containing quinones that show activity in enhance DNA repair and/or prevent damage to DNA and/or upregulate genes associated with wound healing. The quinones are thymoquinone, lapachol, myrtucommulone C, or mixtures thereof, and can be formulated into cosmetic compositions for topical administration to a subject in need thereof. The cosmetic compositions can also include sunscreens, surfactants, sunless tanning agents, desquamation agents, antiperspirants, colorants, preservatives and mixtures; and a cosmetically acceptable carrier. The compositions should find use in methods for treating the signs of ageing in mammals, dermatitis and wound healing via topical application to a site in need thereof, such as the skin or hair of the mammals or a wound site.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.15/803,311, filed Nov. 3, 2017, which claims priority to U.S.Provisional Application No. 62/417,001, filed in the U.S. Patent andTrademark Office on Nov. 3, 2016, the disclosures of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention is in the field of cosmetic compositions, particularlycosmetic compositions containing skin healing and hair protectivequinones, and their topical use in methods improving the appearance ofskin.

BACKGROUND OF THE INVENTION

Many cosmetic compositions utilize chemicals that can be harsh, impairand/or irritate the dermal layers and harm hair. For instance, popularsunscreen agents such as Avobenzone in use have side effects includingcontact dermatitis, acne, rash, and inflammation of hair follicles.Keratolytic agents such as alpha hydroxy acids and many retinoids arerecognized to sting and inflame skin. Emulsifiers and surfactants,particularly sulfates and sulfonates, withdraw protective oils from thedermis leaving behind cracked skin and redness. Sunless tanners undergochemical reactions with amino acids of the epidermis. Antiperspirantsalts can induce skin inflammation. Colorants amongst which arep-phenylenediamines have been implicated as mutagenic and carcinogenic.Preservatives such as nitrites can convert to N-nitrosoamines which areknown carcinogens. In some measure, all the aforementioned materialscause or have potential to cause DNA damage to skin or hair. Variousapproaches have been used to counteract the damage, particularly agentsthat repair DNA.

U.S. Pat. No. 8,513,181 B2 (Zhou) describes methods of preventing ortreating conditions associated with DNA damage. The methods andcompositions focus on substances interfering with activity of the CUL4Aubiquitin ligase bio target.

U.S. Pat. No. 8,535,740 (Babish et al) reports an improved process forrecovery of thymoquinone and use thereof in dietary supplements ortherapeutics against inflammation related disorders. Other thymoquinonerelated documents include U.S. Pat. No. 9,180,155 (Babish), U.S. Pat.No. 8,895,625 (Alkarfy), U.S. Pat. No. 8,501,250 (Ismail), U.S. Pat. No.8,841,264 (Raederstorff), U.S. Pat. No. 8,703,205 (Alzahrani), U.S. Pat.No. 8,586,629 (De Groote), U.S. Pat. No. 8,367,121 (Mazzio), and U.S.Pat. No. 8,029,831 (Pacioretty).

U.S. Pat. No. 7,550,014 (Greaves) reports lapachol in a hair dyeingcomposition. U.S. Pat. No. 6,576,660 (Liao) describes lapachol instudies using 5-alpha reductase. U.S. Pat. No. 6,458,974 (Jiang)describes a synthesis of lapachol and conversion to beta lapachone.

A series of patents describes bioactivity, processes and compositionsrelated to myrtucommulone. These include U.S. Pat. No. 7,910,139(Bombardelli), U.S. Pat. No. 8,192,767 (Carta), U.S. Pat. No. 8,137,707(Paufique), and US 2008/0269510 (Rahman).

Nonetheless, there remains a need to develop compositions that preventdamage to DNA, skin, hair or a combination thereof, caused by componentsof cosmetic formulations.

Therefore, it is an object of the invention to provide compositions thatinhibit damage to DNA, skin, hair, or a combination thereof.

It is also an object of the present invention to provide compositionsthat reduce inflammatory responses associated with various skinconditions including wounds.

It is still an object of the present invention to provide a method oftreating conditions associated with DNA damage and aberrant inflammatoryresponses.

SUMMARY OF THE INVENTION

Described herein are compositions containing quinones that show activityin preventing damage to DNA and/or enhance DNA repair, wound healingand/or dermatitis. In some forms, the quinones are present in aneffective amount to inhibit cullin 4A (CUL4A) ubiquitin ligase and/orupregulate expression of one or more genes selected from the groupconsisting of inteleukin-6 (IL-6), IL1RL1, fibroblast growth factor(FGF), GPHR, ADAM17 and VEGF. In some forms, the quinones constitutefrom 0.001% to 50% by weight of the composition, preferably, between0.001 to 10% by weight of the composition. Preferably, the quinones arethymoquinone, lapachol, myrtucommulone C, or a combination thereof. Thequinones can be formulated into cosmetic compositions for topicaladministration to a subject. In some forms, the cosmetic compositionalso includes sunscreens, surfactants, sunless tanning agents,desquamation agents, antiperspirants, colorants, preservatives, ormixtures thereof, preferably in amounts ranging from 0.1% to 50% byweight of the composition. In some forms, the cosmetic composition alsoincludes a cosmetically acceptable carrier.

Also described are methods for treating the signs of ageing in mammalsincluding topically applying to the skin or hair of the mammals acomposition containing the quinones describe herein. Preferably, thecomposition is a cosmetic composition.

Also disclosed are methods for improving the speed and efficiency ofwound healing, improving collagen deposition at a site in need thereofand to reduce inflammation within the context of skin dermatitis. Thedisclosed formulations can be applied topically to skin wounds toimprove the speed and efficiency of the healing process, to reduce oneor more symptoms associated with skin dermatitis or to improve collagendeposition, for example, in aging skin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B are column charts showing the effects of threecompounds, compared to controls, on percent DNA damage by ultraviolet(UV) exposure in fibroblasts (FIG. 1A) and keratinocytes (FIG. 1B). Dataare shown as mean±SD (n=3). The compounds are indicated as follows:RGN1518, myrtucommulone C; RGN1534, thymoquinone; and RGN1538, lapachol.

FIG. 2A is a bar graph showing cell viability in human keratinocytesfollowing RGN1518 and RGN1538 treatment. Keratinocytes viability wasevaluated after 24 h treatments. Values are calculated as percentage ofthe average±standard error relative to untreated control. Red arrows andvalues indicate cytotoxicity. FIG. 2B is a bar graph showingcytotoxicity of RGN1518 and RGN1538 in human fibroblasts. Fibroblastsviability was evaluated after 24 h treatments. Values are calculated aspercentage of the average±standard error relative to untreated control.Red arrows and values indicate cytotoxicity

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

“Cosmetic composition” as used herein, refers to a composition fortopical application to skin or hair of mammals, especially humans. Sucha composition may be generally classified as leave-on or rinse off, andincludes any product applied to a human body for improving appearance,cleansing, odor control or general aesthetics.

“Derivative” as relates to a given compound, refers to another compoundthat is structurally similar, functionally similar, or both, to thespecified compound. Structural similarity can be determined using anycriterion known in the art, such as the Tanimoto coefficient thatprovides a quantitative measure of similarity between two compoundsbased on their molecular descriptors. Preferably, the moleculardescriptors are 2D properties such as fingerprints, topological indices,and maximum common substructures, or 3D properties such as overallshape, and molecular fields. Tanimoto coefficients range between zeroand one, inclusive, for dissimilar and identical pairs of molecules,respectively. A compound can be considered a derivative of a specifiedcompound, if it has a Tanimoto coefficient with the specified compoundbetween 0.5 and 1.0, inclusive, preferably between 0.7 and 1.0,inclusive, most preferably between 0.85 and 1.0, inclusive. A compoundis functionally similar to a specified compound, if it induces the samepharmacological effect, physiological effect, or both, as the specifiedcompound. “Derivative” can also refer to a modification including, butnot limited to, hydrolysis, reduction, or oxidation products, of thedisclosed compounds. Hydrolysis, reduction, and oxidation reactions areknown in the art.

“Effective amount” and “therapeutically effective amount,” usedinterchangeably, as applied to the nanoparticles, therapeutic agents,and pharmaceutical compositions described herein, mean the quantitynecessary to render the desired therapeutic result. For example, aneffective amount is a level effective to treat, cure, or alleviate thesymptoms of a disease for which the composition and/or therapeuticagent, or pharmaceutical composition, is/are being administered. Amountseffective for the particular therapeutic goal sought will depend upon avariety of factors including the disease being treated and its severityand/or stage of development/progression; the bioavailability andactivity of the specific compound and/or antineoplastic, orpharmaceutical composition, used; the route or method of administrationand introduction site on the subject; the rate of clearance of thespecific composition and other pharmacokinetic properties; the durationof treatment; inoculation regimen; drugs used in combination orcoincident with the specific composition; the age, body weight, sex,diet, physiology and general health of the subject being treated; andlike factors well known to one of skill in the relevant scientific art.Some variation in dosage will necessarily occur depending upon thecondition of the subject being treated, and the physician or otherindividual administering treatment will, in any event, determine theappropriate dosage for an individual patient.

The terms “inhibit” and “reduce” means to reduce or decrease in activityor expression. This can be a complete inhibition or reduction ofactivity or expression, or a partial inhibition or reduction. Inhibitionor reduction can be compared to a control or to a standard level.Inhibition can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%.

The term “substantially free,” describes a composition that has anamount of a component that is at most 10% by weight of the total weightof the sample, as measured an analytical method such as nuclear magneticresonance spectroscopy. Useful examples of “substantially free” includeless than 5% by weight, less than 4% by weight, less than 3% by weight,less than 2% by weight, less than 1% by weight, less than 0.5% wt/wt,less than 0.1% wt/wt, or 0% wt/wt of the sample.

As used herein, a “topical formulation” refers to a composition that isadministered to the surface of the skin.

The term “volatile” as used herein refers to those materials which havea measurable vapor pressure at ambient temperature.

“Substituted” refers to all permissible substituents of the compounds orfunctional groups described herein. In the broadest sense, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,but are not limited to, halogens, hydroxyl groups, or any other organicgroupings containing any number of carbon atoms, preferably 1-14 carbonatoms, and optionally include one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats. Representative substituents include alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl,substituted phenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy,substituted phenoxy, aroxy, substituted aroxy, alkylthio, substitutedalkylthio, phenylthio, substituted phenylthio, arylthio, substitutedarylthio, cyano, isocyano, substituted isocyano, carbonyl, substitutedcarbonyl, carboxyl, substituted carboxyl, amino, substituted amino,amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid,phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl,polyaryl, substituted polyaryl, C₃-C₂₀ cyclic, substituted C₃-C₂₀cyclic, heterocyclic, substituted heterocyclic, amino acid,poly(lactic-co-glycolic acid), peptide, and polypeptide groups. Suchalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, sulfonyl, substitutedsulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl,substituted phosphonyl, polyaryl, substituted polyaryl, C₃-C₂₀ cyclic,substituted C₃-C₂₀ cyclic, heterocyclic, substituted heterocyclic, aminoacid, poly(lactic-co-glycolic acid), peptide, and polypeptide groups canbe further substituted.

Heteroatoms such as nitrogen may have hydrogen sub stituents and/or anypermissible substituents of organic compounds described herein whichsatisfy the valences of the heteroatoms. It is understood that“substitution” or “substituted” includes the implicit proviso that suchsubstitution is in accordance with permitted valence of the substitutedatom and the substituent, and that the substitution results in a stablecompound, i.e. a compound that does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.

“Alkyl,” as used herein, refers to the radical of saturated aliphaticgroups, including straight-chain alkyl groups, branched-chain alkyl,cycloalkyl (alicyclic), alkyl substituted cycloalkyl groups, andcycloalkyl substituted alkyl. In preferred forms, a straight chain orbranched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g.,C₁-C₃₀ for straight chains, C₃-C₃₀ for branched chains), preferably 20or fewer, more preferably 15 or fewer, most preferably 10 or fewer.Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl,eicosyl, tetracosyl and the like.

Preferred cycloalkyls have from 3-10 carbon atoms in their ringstructure, and more preferably have 5, 6 or 7 carbons in the ringstructure. The term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls,” the latter of whichrefers to alkyl moieties having one or more substituents replacing ahydrogen on one or more carbons of the hydrocarbon backbone. Suchsubstituents include, but are not limited to, halogen, hydroxyl,carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl),thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),alkoxyl, phosphoryl, phosphate, phosphonate, a phosphinate, amino,amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl,aralkyl, or an aromatic or heteroaromatic moiety.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, more preferably from one to six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths. Throughout the application, preferred alkylgroups are lower alkyls. In preferred forms, a substituent designatedherein as alkyl is a lower alkyl.

“Alkyl” includes one or more substitutions at one or more carbon atomsof the hydrocarbon radical as well as heteroalkyls. Suitablesubstituents include, but are not limited to, halogens, such asfluorine, chlorine, bromine, or iodine; hydroxyl; —NRR′, wherein R andR′ are independently hydrogen, alkyl, or aryl, and wherein the nitrogenatom is optionally quaternized; —SR, wherein R is hydrogen, alkyl, oraryl; —CN; —NO₂; —COOH; carboxylate; —COR, —COOR, or —CON(R)₂, wherein Ris hydrogen, alkyl, or aryl; azide, aralkyl, alkoxyl, imino,phosphonate, phosphinate, silyl, ether, sulfonyl, sulfonamido,heterocyclyl, aromatic or heteroaromatic moieties, haloalkyl (such as—CF₃, —CH₂—CF₃, —CCl₃); —CN; —NCOCOCH₂CH₂, —NCOCOCHCH; —NCS; andcombinations thereof.

It will be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate. For instance, the substituents of a substituted alkyl mayinclude halogen, hydroxy, nitro, thiols, amino, azido, imino, amido,phosphoryl (including phosphonate and phosphinate), sulfonyl (includingsulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, aswell as ethers, alkylthios, carbonyls (including ketones, aldehydes,carboxylates, and esters), haloalkyls, —CN and the like. Cycloalkyls canbe substituted in the same manner.

“Heteroalkyl,” as used herein, refers to straight or branched chain, orcyclic carbon-containing radicals, or combinations thereof, containingat least one heteroatom. Suitable heteroatoms include, but are notlimited to, O, N, Si, P and S, wherein the nitrogen, phosphorous andsulfur atoms are optionally oxidized, and the nitrogen heteroatom isoptionally quaternized.

The terms “alkoxyl” or “alkoxy,” “aroxy” or “aryloxy,” generallydescribe compounds represented by the formula —OR^(v), wherein RVincludes, but is not limited to, substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl,heterocycloalkenyl, aryl, heteroaryl, arylalkyl, heteroalkyls,alkylaryl, alkylheteroaryl.

The terms “alkoxyl” or “alkoxy” as used herein refer to an alkyl group,as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as can berepresented by one of —O-alkyl, —O-alkenyl, and —O— alkynyl. The termalkoxy also includes cycloalkyl, heterocyclyl, cycloalkenyl,heterocycloalkenyl, and arylalkyl having an oxygen radical attached toat least one of the carbon atoms, as valency permits. A “lower alkoxy”group is an alkoxy group containing from one to six carbon atoms.

The term “substituted alkoxy” refers to an alkoxy group having one ormore substituents replacing one or more hydrogen atoms on one or morecarbons of the alkoxy backbone. Such substituents include, but are notlimited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl,alkylaryl, haloalkyl, —CN, aryl, heteroaryl, and combinations thereof.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms and structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (AB)C=C(CD) areintended to include both the E and Z isomers. This may be presumed instructural formulae herein wherein an asymmetric alkene is present, orit may be explicitly indicated by the bond symbol C.

The term “alkynyl group” as used herein is a hydrocarbon group of 2 to24 carbon atoms and a structural formula containing at least onecarbon-carbon triple bond.

The term “aryl” as used herein is any C₅-C₂₆ carbon-based aromaticgroup, fused aromatic, fused heterocyclic, or biaromatic ring systems.Broadly defined, “aryl,” as used herein, includes 5-, 6-, 7-, 8-, 9-,10-, 14-, 18-, and 24-membered single-ring aromatic groups, including,but not limited to, benzene, naphthalene, anthracene, phenanthrene,chrysene, pyrene, corannulene, coronene, etc. “Aryl” further encompassespolycyclic ring systems having two or more cyclic rings in which two ormore carbons are common to two adjoining rings (i.e., “fused rings”)wherein at least one of the rings is aromatic, e.g., the other cyclicring or rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocycles. The aryl group can be substituted with one or moregroups including, but not limited to, alkyl, alkynyl, alkenyl, aryl,halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid,or alkoxy.

The term “substituted aryl” refers to an aryl group, wherein one or morehydrogen atoms on one or more aromatic rings are substituted with one ormore substituents including, but not limited to, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (suchas a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl),silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate,or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate,phosphinate, amino (or quarternized amino), amido, amidine, imine,cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate,sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl(such as CF₃, —CH₂—CF₃, —CCl₃), —CN, aryl, heteroaryl, and combinationsthereof.

“Heterocycle,” “heterocyclic” and “heterocyclyl” are usedinterchangeably, and refer to a cyclic radical attached via a ringcarbon or nitrogen atom of a monocyclic or bicyclic ring containing 3-10ring atoms, and preferably from 5-6 ring atoms, consisting of carbon andone to four heteroatoms each selected from the group consisting ofnon-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O,C₁-C₁₀ alkyl, phenyl or benzyl, and optionally containing 1-3 doublebonds and optionally substituted with one or more substituents.Heterocyclyl are distinguished from heteroaryl by definition. Examplesof heterocycles include, but are not limited to piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl,dihydrofuro[2,3-b]tetrahydrofuran, morpholinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl,2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl,6H-1,2,5-thiadiazinyl. Heterocyclic groups can optionally be substitutedwith one or more substituents as defined above for alkyl and aryl.

The term “heteroaryl” refers to C₅-C₂₆-membered aromatic, fusedaromatic, biaromatic ring systems, or combinations thereof, in which oneor more carbon atoms on one or more aromatic ring structures have beensubstituted with a heteroatom. Suitable heteroatoms include, but are notlimited to, oxygen, sulfur, and nitrogen. Broadly defined, “heteroaryl,”as used herein, includes 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and24-membered single-ring aromatic groups that may include from one tofour heteroatoms, for example, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyridazine and pyrimidine, and the like. The heteroaryl group may alsobe referred to as “aryl heterocycles” or “heteroaromatics”. “Heteroaryl”further encompasses polycyclic ring systems having two or more rings inwhich two or more carbons are common to two adjoining rings (i.e.,“fused rings”) wherein at least one of the rings is heteroaromatic,e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heterocycles, or combinations thereof. Examples ofheteroaryl rings include, but are not limited to, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl,octahydroisoquinolinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or moreof the rings can be substituted as defined below for “substitutedheteroaryl”.

The term “substituted heteroaryl” refers to a heteroaryl group in whichone or more hydrogen atoms on one or more heteroaromatic rings aresubstituted with one or more substituents including, but not limited to,halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl,alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino,alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl (such as CF₃, —CH₂—CF₃, —CCl₃), —CN,aryl, heteroaryl, and combinations thereof.

The term “substituted alkenyl” refers to alkenyl moieties having one ormore substituents replacing one or more hydrogen atoms on one or morecarbons of the hydrocarbon backbone. Such substituents include, but arenot limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl,alkylaryl, haloalkyl, —CN, aryl, heteroaryl, and combinations thereof.

The term “substituted alkynyl” refers to alkynyl moieties having one ormore substituents replacing one or more hydrogen atoms on one or morecarbons of the hydrocarbon backbone. Such substituents include, but arenot limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl,alkylaryl, haloalkyl, —CN, aryl, heteroaryl, and combinations thereof.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc. The term “heterocycloalkyl group” is a cycloalkyl groupas defined above where at least one of the carbon atoms of the ring issubstituted with a heteroatom such as, but not limited to, nitrogen,oxygen, sulphur, or phosphorus.

The term “aralkyl” as used herein is an aryl group having an alkyl,alkynyl, or alkenyl group as defined above attached to the aromaticgroup. An example of an aralkyl group is a benzyl group.

The term “hydroxyalkyl group” as used herein is an alkyl, alkenyl,alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, orheterocycloalkyl group described above that has at least one hydrogenatom substituted with a hydroxyl group.

The term “alkoxyalkyl group” is defined as an alkyl, alkenyl, alkynyl,aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl groupdescribed above that has at least one hydrogen atom substituted with analkoxy group described above.

“Carbonyl,” as used herein, is art-recognized and includes such moietiesas can be represented by the general formula:

wherein X is a bond, or represents an oxygen or a sulfur, and Rrepresents a hydrogen, a substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted alkylaryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, —(CH₂)_(m)—R″, or apharmaceutical acceptable salt, R′ represents a hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedalkylaryl, substituted or unsubstituted arylalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl or—(CH₂)_(m)—R″; R″ represents a hydroxy group, substituted orunsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenylring, a heterocycle, or a polycycle; and m is zero or an integer rangingfrom 1 to 8. Where X is oxygen and R is defines as above, the moiety isalso referred to as a carboxyl group. When X is oxygen and R ishydrogen, the formula represents a ‘carboxylic acid’. Where X is oxygenand R′ is hydrogen, the formula represents a ‘formate’. Where X isoxygen and R or R′ is not hydrogen, the formula represents an “ester”.In general, where the oxygen atom of the above formula is replaced by asulfur atom, the formula represents a ‘thiocarbonyl’ group. Where X issulfur and R or R′ is not hydrogen, the formula represents a‘thioester.’ Where X is sulfur and R is hydrogen, the formula representsa ‘thiocarboxylic acid.’ Where X is sulfur and R′ is hydrogen, theformula represents a ‘thioformate.’ Where X is a bond and R is nothydrogen, the above formula represents a ‘ketone.’ Where X is a bond andR is hydrogen, the above formula represents an ‘aldehyde.’

The term “substituted carbonyl” refers to a carbonyl, as defined above,wherein one or more hydrogen atoms in R, R′ or a group to which themoiety

is attached, are independently substituted. Such substituents include,but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl,alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl(such as a thioester, a thioacetate, or a thioformate), alkoxyl,phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternizedamino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl,alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “carboxyl” is as defined above for the formula

and is defined more specifically by the formula —R^(iv)COOH, whereinR^(iv) is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,alkylaryl, arylalkyl, aryl, or heteroaryl. In preferred forms, astraight chain or branched chain alkyl, alkenyl, and alkynyl have 30 orfewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straight chainalkyl, C₃-C₃₀ for branched chain alkyl, C₂-C₃₀ for straight chainalkenyl and alkynyl, C₃-C₃₀ for branched chain alkenyl and alkynyl),preferably 20 or fewer, more preferably 15 or fewer, most preferably 10or fewer. Likewise, preferred cycloalkyls, heterocyclyls, aryls andheteroaryls have from 3-10 carbon atoms in their ring structure, andmore preferably have 5, 6 or 7 carbons in the ring structure.

The term “substituted carboxyl” refers to a carboxyl, as defined above,wherein one or more hydrogen atoms in R^(iv) are substituted. Suchsubstituents include, but are not limited to, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as acarboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester,thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (orquarternized amino), amido, amidine, imine, cyano, nitro, azido,sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido,sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “phenoxy” is art recognized, and refers to a compound of theformula —OR^(v) wherein RV is (i.e., —O—C₆H₅). One of skill in the artrecognizes that a phenoxy is a species of the aroxy genus.

The term “substituted phenoxy” refers to a phenoxy group, as definedabove, having one or more substituents replacing one or more hydrogenatoms on one or more carbons of the phenyl ring. Such substituentsinclude, but are not limited to, halogen, azide, alkyl, aralkyl,alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl,alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl(such as a thioester, a thioacetate, or a thioformate), alkoxyl,phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternizedamino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl,alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The terms “aroxy” and “aryloxy,” as used interchangeably herein, arerepresented by —O-aryl or —O-heteroaryl, wherein aryl and heteroaryl areas defined herein.

The terms “substituted aroxy” and “substituted aryloxy,” as usedinterchangeably herein, represent —O-aryl or —O-heteroaryl, having oneor more substituents replacing one or more hydrogen atoms on one or morering atoms of the aryl and heteroaryl, as defined herein. Suchsubstituents include, but are not limited to, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as acarboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester,thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (orquarternized amino), amido, amidine, imine, cyano, nitro, azido,sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido,sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur radical attached thereto. The “alkylthio” moiety is representedby —S-alkyl. Representative alkylthio groups include methylthio,ethylthio, and the like. The term “alkylthio” also encompassescycloalkyl groups having a sulfur radical attached thereto.

The term “substituted alkylthio” refers to an alkylthio group having oneor more substituents replacing one or more hydrogen atoms on one or morecarbon atoms of the alkylthio backbone. Such substituents include, butare not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl,alkylaryl, haloalkyl, —CN, aryl, heteroaryl, and combinations thereof.

The term “phenylthio” is art recognized, and refers to —S—C₆H5, i.e., aphenyl group attached to a sulfur atom.

The term “substituted phenylthio” refers to a phenylthio group, asdefined above, having one or more substituents replacing a hydrogen onone or more carbons of the phenyl ring. Such substituents include, butare not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl,alkylaryl, haloalkyl, —CN, aryl, heteroaryl, and combinations thereof.

“Arylthio” refers to —S-aryl or —S-heteroaryl groups, wherein aryl andheteroaryl as defined herein.

The term “substituted arylthio” represents —S-aryl or —S-heteroaryl,having one or more substituents replacing a hydrogen atom on one or morering atoms of the aryl and heteroaryl rings as defined herein. Suchsubstituents include, but are not limited to, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as acarboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester,thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (orquarternized amino), amido, amidine, imine, cyano, nitro, azido,sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido,sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The terms “amide” or “amido” are used interchangeably, refer to both“unsubstituted amido” and “substituted amido” and are represented by thegeneral formula:

wherein, E is absent, or E is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aralkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl,wherein independently of E, R and R′ each independently represent ahydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbonyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedalkylaryl, substituted or unsubstituted arylalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl,—(CH₂)_(m)—R′″, or R and R′ taken together with the N atom to which theyare attached complete a heterocycle having from 3 to 14 atoms in thering structure; R′″ represents a hydroxy group, substituted orunsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenylring, a heterocycle, or a polycycle; and m is zero or an integer rangingfrom 1 to 8. In preferred forms, only one of R and R′ can be a carbonyl,e.g., R and R′ together with the nitrogen do not form an imide. Inpreferred forms, R and R′ each independently represent a hydrogen atom,substituted or unsubstituted alkyl, a substituted or unsubstitutedalkenyl, or —(CH₂)_(m)—R′″. When E is oxygen, a carbamate is formed. Thecarbamate cannot be attached to another chemical species, such as toform an oxygen-oxygen bond, or other unstable bonds, as understood byone of ordinary skill in the art.

The term “sulfonyl” is represented by the formula

wherein E is absent, or E is alkyl, alkenyl, alkynyl, aralkyl,alkylaryl, cycloalkyl, aryl, heteroaryl, heterocyclyl, whereinindependently of E, R represents a hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted amine,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted alkylaryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, —(CH₂)_(m)—R′″, or E and Rtaken together with the S atom to which they are attached complete aheterocycle having from 3 to 14 atoms in the ring structure; R′″represents a hydroxy group, substituted or unsubstituted carbonyl group,an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, or apolycycle; and m is zero or an integer ranging from 1 to 8. In preferredforms, only one of E and R can be substituted or unsubstituted amine, toform a “sulfonamide” or “sulfonamido.” The substituted or unsubstitutedamine is as defined above.

The term “substituted sulfonyl” represents a sulfonyl in which E, R, orboth, are independently substituted. Such substituents include, but arenot limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl,alkylaryl, haloalkyl, —CN, aryl, heteroaryl, and combinations thereof.

The term “sulfonic acid” refers to a sulfonyl, as defined above, whereinR is hydroxyl, and E is absent, or E is substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted alkylaryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

The term “sulfate” refers to a sulfonyl, as defined above, wherein E isabsent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy,as defined above, and R is independently hydroxyl, alkoxy, aroxy,substituted alkoxy or substituted aroxy, as defined above. When E isoxygen, the sulfate cannot be attached to another chemical species, suchas to form an oxygen-oxygen bond, or other unstable bonds, as understoodby one of ordinary skill in the art.

The term “sulfonate” refers to a sulfonyl, as defined above, wherein Eis oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, asdefined above, and R is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted amine,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted alkylaryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, —(CH₂)_(m)—R′″, R′″ representsa hydroxy group, substituted or unsubstituted carbonyl group, an aryl, acycloalkyl ring, a cycloalkenyl ring, a heterocycle, or a polycycle; andm is zero or an integer ranging from 1 to 8. When E is oxygen, sulfonatecannot be attached to another chemical species, such as to form anoxygen-oxygen bond, or other unstable bonds, as understood by one ofordinary skill in the art.

The term “sulfamoyl” refers to a sulfonamide or sulfonamide representedby the formula

wherein E is absent, or E is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aralkyl, substituted orunsubstituted alkylaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocyclyl, whereinindependently of E, R and R′ each independently represent a hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbonyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedalkylaryl, substituted or unsubstituted arylalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl,—(CH₂)_(m)—R′″, or R and R′ taken together with the N atom to which theyare attached complete a heterocycle having from 3 to 14 atoms in thering structure; R′″ represents a hydroxy group, substituted orunsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenylring, a heterocycle, or a polycycle; and m is zero or an integer rangingfrom 1 to 8. In preferred forms, only one of R and R′ can be a carbonyl,e.g., R and R′ together with the nitrogen do not form an imide.

The term “phosphonyl” is represented by the formula

wherein E is absent, or E is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aralkyl, substituted orunsubstituted alkylaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocyclyl, wherein,independently of E, R^(vi) and R^(vii) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbonyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedalkylaryl, substituted or unsubstituted arylalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl,—(CH₂)_(m)—R′″, or R and R′ taken together with the P atom to which theyare attached complete a heterocycle having from 3 to 14 atoms in thering structure; R′″ represents a hydroxy group, substituted orunsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenylring, a heterocycle, or a polycycle; and m is zero or an integer rangingfrom 1 to 8.

The term “substituted phosphonyl” represents a phosphonyl in which E,R^(vi) and R^(vii) are independently substituted. Such substituentsinclude, but are not limited to, halogen, azide, alkyl, aralkyl,alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl,alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl(such as a thioester, a thioacetate, or a thioformate), alkoxyl,phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternizedamino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl,alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “phosphoryl” defines a phosphonyl in which E is absent, oxygen,alkoxy, aroxy, substituted alkoxy or substituted aroxy, as definedabove, and independently of E, R^(vi) and R^(vii) are independentlyhydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy, asdefined above. When E is oxygen, the phosphoryl cannot be attached toanother chemical species, such as to form an oxygen-oxygen bond, orother unstable bonds, as understood by one of ordinary skill in the art.When E, R^(vi) and R^(vii) are substituted, the substituents include,but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl,alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl(such as a thioester, a thioacetate, or a thioformate), alkoxyl,phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternizedamino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl,alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “polyaryl” refers to a chemical moiety that includes two ormore aryls, heteroaryls, and combinations thereof. The aryls,heteroaryls, and combinations thereof, are fused, or linked via a singlebond, ether, ester, carbonyl, amide, sulfonyl, sulfonamide, alkyl, azo,and combinations thereof. When two or more heteroaryls are involved, thechemical moiety can be referred to as a “polyheteroaryl.”

The term “substituted polyaryl” refers to a polyaryl in which one ormore of the aryls, heteroaryls are substituted, with one or moresubstituents including, but not limited to, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as acarboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester,thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (orquarternized amino), amido, amidine, imine, cyano, nitro, azido,sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido,sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof. When two or more heteroaryls are involved, thechemical moiety can be referred to as a “substituted polyheteroaryl.”

The term “C₃-C₂₀ cyclic” refers to a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted orunsubstituted cycloalkynyl, substituted or unsubstituted heterocyclylthat have from three to 20 carbon atoms, as geometric constraintspermit. The cyclic structures are formed from single or fused ringsystems. The substituted cycloalkyls, cycloalkenyls, cycloalkynyls andheterocyclyls are substituted as defined above for the alkyls, alkenyls,alkynyls and heterocyclyls, respectively.

The term “ether” as used herein is represented by the formula AOA¹,where A and A¹ can be, independently, an alkyl, halogenated alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl group described above.

The term “urethane” as used herein is represented by the formula—OC(O)NRR′, where R and R′ can be, independently, hydrogen, an alkyl,alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, orheterocycloalkyl group described above.

The term “silyl group” as used herein is represented by the formula—SiRR′R″, where R, R′, and R″ can be, independently, hydrogen, an alkyl,alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, alkoxy,or heterocycloalkyl group described above.

The terms “hydroxyl” and “hydroxy” are used interchangeably and arerepresented by —OH.

The terms “thiol” and “sulfhydryl” are used interchangeably and arerepresented by —SH.

The term “oxo” refers to ═O bonded to a carbon atom.

The terms “cyano” and “nitrile” are used interchangeably to refer to—CN.

The term “nitro” refers to —NO₂.

The term “phosphate” refers to —O—PO₃.

The term “azide” or “azido” are used interchangeably to refer to —N₃.The term “substituted C₁-C_(x) alkyl” refers to alkyl groups having fromone to x carbon atoms, wherein at least one carbon atom is substituted,wherein “x” is an integer from one to ten. The term “unsubstitutedC₁-C_(x) alkyl” refers to alkyl groups having from one to x carbon atomsthat are not substituted, wherein “x” is an integer from one to ten.

The term “substituted C₂-C_(x) alkenyl” refers to alkenyl groups havingfrom two to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from two to ten. The term“unsubstituted C₂-C_(x) alkenyl” refers to alkenyl groups having fromtwo to x carbon atoms that are not substituted, wherein “x” is aninteger from two to ten.

The term “substituted C₁-C_(x) carbonyl” refers to carbonyl groupshaving from one to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) carbonyl” refers to carbonyl groups having fromone to x carbon atoms that are not substituted, wherein “x” is aninteger from one to ten.

II. Composition

Many components found in cosmetic compositions damage skin and hair.Amongst these components are certain types of sunscreens, thickeners,surfactants, sunless tanners, desquamation agents, antiperspirants,colorants, preservatives and mixtures thereof. Some of these damageinvolves damage to DNA.

It is now been found that certain quinones have activity in avoiding andrepairing damage to DNA, in particular mammalian DNA. It has also beendiscovered that certain quinones have activity in upregulating importantgenes involved in wound healing and anti-inflammatory response.Accordingly, the quinones can be used to treat conditions involving DNAdamage or used to enhance DNA repair, wound healing and/or dermatitis.Described herein, are compositions containing the quinones. In someforms, the compositions are formulated into cosmetic compositions.Preferably, the cosmetic compositions minimize damage caused by theaforementioned components. In some forms, the cosmetic compositions canalso contain a cosmetically acceptable carrier such as water;emollients; hydrocarbons; fatty acids; fatty alcohols; humectants; skinlighteners; active peptides; vitamins; additional materials such asresveratrol, etc.; or combinations thereof.

In some forms, the quinone(s) is present in the composition in aneffective amount to inhibit cullin 4A (CUL4A) ubiquitin ligase activity,as measured using an assay that measures DNA damage in a cell, in termsof the formation of cyclobutane pyrimidine dimers in DNA. In some forms,the quinone is present in an effective amount to enhance DNA repair.Exemplary assays to measure CUL4A inhibition or enhancement of DNArepair are described below in Example 1.

Advantageously, UV irradiated samples of the quinone or cosmeticcompositions formulated with the quinone exhibit, in testing against theCUL4 bio target, a reduction in DNA damage relative to a UV irradiatedcontrol of at least 10%, preferably at least 50%, and more preferably byat least 80% over baseline compared to a no treatment control forexample, DMSO as measured by % CPD (Cyclobutane Pyrimidine Dimer) formedin a test cell. In most preferred embodiments the inhibition is between80% and 120%, for example, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 115%,118%, and 120%. Accordingly, the compositions should be useful in DNArepair, particularly in skin cells.

In some forms, the cosmetic composition does not contain apharmaceutical grade methionine, an extract from cranberry, cranberryjuice, or a combination thereof.

In some forms, besides quinones described herein, the cosmeticcomposition is substantially free of one or more additional essentialoil components extracted from the seed of Nigella sativa. For example,the disclosed compositions use pure Thymoquinone and include less 5% byweight, less than 4% by weight, less than 3% by weight, less than 2% byweight, less than 1% by weight, less than 0.5% wt/wt, less than 0.1%wt/wt, or 0% wt/wt of essential oil components extracted from the seedof Nigella sativa, which are invariably are included in supercriticalfluid extracts of Nigella sativa, for example, supercritical CO₂ extractof Nigella sativa seed. Accordingly, in some forms, the thymoquinone inthe disclosed formulations is not a supercritical CO₂ extract of Nigellasativa seed.

In some forms, the cosmetic composition is substantially free of aphenylethanoid, such as hydroxytyrosol.

In some forms, the cosmetic composition is substantially free of a honeyand/or myrth, zinc/zinc supplementation, pyruvate, succinate,alpha-ketoglutarate, oxaloacetate, niacin, fruit extract.

A. Compounds

The compositions contain quinones that have the structural formulaeshown below:

wherein X and Y are independently carbon (C) or CH; Z is hydroxyl oroxygen; and the dashed line between X and Y, and between Y and Z showsthe presence or absence of a bond, depending on the valency of X, Y, andZ;

wherein R1, R2, R3, R4, R5, R6, R7, and R8 are independently hydrogen,unsubstituted C1-C10 alkyl, substituted C1-C10 alkyl, unsubstitutedC2-C10 alkenyl, substituted C2-C10 alkenyl, hydroxyl, thiol, halogen,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy,substituted alkoxy, aroxy, substituted aroxy, alkylthio, substitutedalkylthio, arylthio, substituted arylthio, carbonyl, substitutedcarbonyl, carboxyl, substituted carboxyl, amino, substituted amino,amido, substituted amido, polyaryl, substituted polyaryl, C₃-C₂₀ cyclic,substituted C₃-C₂₀ cyclic, heterocyclic, substituted heterocyclic;

wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21,R22, and R23 are independently hydrogen, unsubstituted C1-C10 alkyl,substituted C1-C10 alkyl, hydroxyl, ═O, substituted C1-C10 carbonyl, orunsubstituted C1-C10 carbonyl, thiol, halogen, aryl, substituted aryl,heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, aroxy,substituted aroxy, alkylthio, substituted alkylthio, arylthio,substituted arylthio, carboxyl, substituted carboxyl, amino, substitutedamino, amido, substituted amido, polyaryl, substituted polyaryl, C₃-C₂₀cyclic, substituted C₃-C₂₀ cyclic, heterocyclic, substitutedheterocyclic.

In some forms of Formula I, R2 is not hydroxyl. In some forms of FormulaI, R4 is not hydroxyl. In some forms of Formula I, R2 and R4 are nothydroxyl. In some forms of Formula I, R1 is not undecyl. In some formsof Formula I, R1 is not undecyl, and R2 and R4 are not hydroxyl. In someforms, the compound of Formula I is not2,5-dihydroxy-3-undecyl-2,5-cyclohexadiene-1,4-dione.

In some forms of Formula I, R2 and R4 are each hydrogen.

In some forms of Formula I, R1 and R3 are independently unsubstitutedC1-C10 alkyl, or substituted C1-C10 alkyl.

In some forms of Formula I, R1 and R3 are independently unsubstitutedC1-C5 alkyl, or substituted C1-C5 alkyl; R2 and R4 are each hydrogen.

In some forms of Formula I, R1 is substituted C1-C5 alkyl; R3 is methyl,and R2 and R4 are each hydrogen.

In some forms of Formula II, R5, R6, R7, and R8 are independentlyhydrogen, C1-C10 alkyl, or substituted C1-C10 alkyl.

In some forms of Formula II, R5, R6, R7, and R8 are hydrogen.

In some forms of Formula II, R1 and R2 are independently unsubstitutedC2-C10 alkenyl, substituted C2-C10 alkenyl, C1-C10 alkyl, substitutedC1-C10 alkyl, or hydroxyl.

In some forms of Formula II, R1 and R2 are independently unsubstitutedC2-C10 alkenyl, substituted C2-C10 alkenyl, or hydroxyl.

In some forms of Formula II, R5, R6, R7, and R8 are independentlyhydrogen, C1-C10 alkyl, or substituted C1-C10 alkyl; R1 and R2 areindependently unsubstituted C2-C10 alkenyl, substituted C2-C10 alkenyl,C1-C10 alkyl, substituted C1-C10 alkyl, or hydroxyl.

In some forms of Formula II, R5, R6, R7, and R8 are hydrogen; R1 and R2are independently unsubstituted C2-C10 alkenyl, substituted C2-C10alkenyl, C1-C10 alkyl, substituted C1-C10 alkyl, or hydroxyl.

In some forms of Formula II, R5, R6, R7, and R8 are hydrogen; R1 and R2are independently unsubstituted C2-C10 alkenyl, substituted C2-C10alkenyl, or hydroxyl.

In some forms of Formula II, R5, R6, R7, and R8 are hydrogen; R1 issubstituted C2-C10 alkenyl, and R2 is hydroxyl.

In some forms of Formula III, R9 is substituted C1-C10 carbonyl.

In some forms of Formula III, R10 is hydroxyl.

In some forms of Formula III, X is carbon (C) or CH, Y is carbon (C), Zis hydroxyl, the dashed line between X and Y is a bond, and the dashedline between Y and Z is absent.

In some forms of Formula III, R11, R12, R13, R14, R15, R16, R18, R19,R20, R21, R22, and R23 are independently hydrogen, substituted C1-C10alkyl, or unsubstituted C1-C10 alkyl.

In some forms of Formula III, R11, R12, R13, R14, R20, R21, R22, and R23are unsubstituted C1-C10 alkyl.

In some forms of Formula III, R15, R16, R18, and R19 are independentlyhydrogen or substituted C1-C10 alkyl.

In some forms of Formula III, R15 and R18 are hydrogen, and R16 and R19are substituted C1-C10 alkyl.

In some forms of Formula III, R17 is hydroxyl.

In some forms of Formula III, R9 is substituted C1-C10 carbonyl; X and Yare carbon (C), Z is hydroxyl, the dashed line between X and Y is abond, and the dashed line between Y and Z is absent; R10 is hydroxyl;R11, R12, R13, R14, R20, R21, R22, and R23 are unsubstituted C1-C10alkyl; R15, R16, R18, and R19 are independently hydrogen or substitutedC1-C10 alkyl; and R17 is hydroxyl.

In some forms of Formula III, R9 is substituted C1-C10 carbonyl; X and Yare carbon (C), Z is hydroxyl, the dashed line between X and Y is abond, and the dashed line between Y and Z is absent; R10 is hydroxyl;R11, R12, R13, R14, R20, R21, R22, and R23 are unsubstituted C1-C10alkyl; R15 and R18 are hydrogen, R16 and R19 are substituted C1-C10alkyl; and R17 is hydroxyl.

In some forms of Formula III, R9 is substituted C1-C5 carbonyl; X and Yare carbon (C), Z is hydroxyl, the dashed line between X and Y is abond, and the dashed line between Y and Z is absent; R10 is hydroxyl;R11, R12, R13, R14, R20, R21, R22, and R23 are unsubstituted C1-C5alkyl; R15 and R18 are hydrogen, R16 and R19 are substituted C1-C5alkyl; and R17 is hydroxyl.

In some forms of Formula III, R9 is substituted C1-C5 carbonyl; X and Yare carbon (C), Z is hydroxyl, the dashed line between X and Y is abond, and the dashed line between Y and Z is absent; R10 is hydroxyl;R11, R12, R13, R14, R20, R21, R22, and R23 are methyl; R15 and R18 arehydrogen, R16 and R19 are substituted C1-C5 alkyl; and R17 is hydroxyl.

In some forms of Formula III, R9 is substituted C1-C5 carbonyl; X and Yare carbon (C), Z is hydroxyl, the dashed line between X and Y is abond, and the dashed line between Y and Z is absent; R10 is hydroxyl;R11, R12, R13, R14, R20, R21, R22, and R23 are methyl; R15 and R18 arehydrogen, R16 and R19 are isopropyl; and R17 is hydroxyl.

Preferred compounds include the following quinones: thymoquinone,lapachol and myrtucommulone C.

Amounts of the quinones may range from 0.001% to 50% by weight, 0.1% to50% by weight, from 0.001% to 20% by weight sometimes from 0.001% to 10%by weight, occasionally from 0.001% to 2% by weight, from 0.001% to 1%by weight, 0.001% to 7.5% by weight, or 0.01% to 5.0% by weight of thecosmetic composition. Exemplary percent compositions include 0.01% byweight, 0.024% by weight, 0.10% by weight, 0.25% by weight, 1.0% byweight, 1.50% by weight, 2.00% by weight, 2.5% by weight, and 5.0% byweight of the composition. When combinations of quinones are utilized,their relative weight amounts may range from 1000:1 to 1:1000,occasionally from 100:1 to 1:100, and even from 10:1 to 1:10. In someforms, the relative weight amounts are the same. For example, when twoquinones are present the relative weight amounts are 1:1; when threequinones are present the relative weight amounts are 1:1:1, etc.

Thymoquinone

In a preferred embodiment, the compound of Formula I is2-isopropyl-5-methylbenzo-1,4-quinone, commonly known as thymoquinone,and has the structural formula below:

Thymoquinone is a phytochemical compound found in the plant NigellaSativa. Also this material may be found in cultivated Monarda Fistulosa.

In a preferred embodiment, the disclosed compositions includethymoquinone monomer or dimer (thymoquinone readily dimerizes to formdithymoquinone. Thymoquinone is included in the formulation in aconcentration ranging from 0.01% to 5% by weight, more preferably,between 0.1% and 3% by weight, inclusive.

Lapachol

In some forms, the compound of Formula II is2-hydroxy-3-(3-methylbut-2-enyl)naphthalene-1,4-dione, commonly known aslapachol, and has the structural formula below:

Lapachol is a natural phenolic compound isolated from the bark of thelapacho tree.

In a preferred embodiment, lapachol is included in the formulation in aconcentration ranging from 0.01% to 5% by weight, more preferably,between 0.01% and 3% by weight, inclusive. In some embodiments, thelapachol is not encapsulated in water impermeable shell, for example, ina lipid, gelatin, calcium aginate, polymethyl methacrylate urea or otherwater impermeable shell. In some forms the formulation does not includecatechins, for example, epicatechin gallate and epigallocatechin; orrosemary plant extracts.

In some forms, the compound of Formula III, is known by the common namemyrtucummulone, and has the structural formula below:

Myrtucommulone is isolated from Myrtus communis and is alsosynthetically available. Among the myrtucommulone family of isomers,stereoisomers and related compounds, is myrtucommulone C which itselfoccurs as two tautomers (interchangeable constitutional isomers). Thechemical structure of myrtucommulone C depicted in its two tautomerinterchangeable forms is shown below:

Each of the tautomers has two chiral centers (denoted by the asterisks)where the optical rotation can be either R or S. Therefore, for eachtautomer it is possible to have four different compounds with R,R; R,S;S,R; and S,S chirality.

In some preferred embodiment, myrtucommulone C is included in theformulation in a concentration ranging from 0.01% to 5% by weight, morepreferably, between 0.01% and 2% by weight, inclusive.

In some preferred embodiments, the myrtucommulone C component (includedin the formulation in a concentration ranging from 0.01% to 5% byweight, more preferably, between 0.01% and 2% by weight, inclusive),contains diatereomers, with have the structures shown below.

Preferably, the myrtucommulone C component included in the sample cancontain between a 40%:60% and a 60% to 40% mixture of the diastereomers,and preferably, not up to 80% of any one of the R*,R* or R*,S*diatereomers. For example, the compositions can the myrtucommulone Ccomponent a 50% to 50% mixture of the R*,R* and R*,S* diatereomers, 41%to 58% mixture of the R*,R* and R*,S* diastereomer; a 42% to 58% mixtureof the R*,R* and R*,S* diastereomer, 43% to 57% mixture of the R*,R* andR*,S* diastereomer; 44% to 56% mixture of the R*,R* and R*,S*diastereomer; 45%:55% mixture of the R*,R* and R*,S* diastereomer, etc.,and vice versa.

Optionally, the formulations may include myrtucommulone A, B, D and/orE. In some embodiment, the formulations do not include myrtucommulone A,B, D and/or E.

The examples below show that thymoquinone, lapachol, myrtucommulone, andmixtures thereof can function as skin and/or hair protective or healingagents to repair damaged DNA. Among the myrtucommulone isomers, we foundmyrtucommulone C to be most effective. Combinations of the quinones canbe particularly active. For instance, combinations of thymoquinone andlapachol have shown synergistic effect.

B. Formulations

Suitable dosage forms for topical administration include creams,ointments, salves, sprays, gels, lotions, emulsions, and transdermalpatches. The formulation may be formulated for transmucosal,transepithelial, transendothelial, or transdermal administration. Theformulations can include known excipients used in topical formulations,included but not limited to sunscreens, surfactants, preservatives,desquamation agents, antiperspirants, colorants, thickeners, skinlighteners, vitamins and other therapeutically active agents in acosmetically acceptable carrier.

The cosmetic compositions may be formulated into a wide variety ofproduct types that include, but are not limited to, solutions;suspensions; lotions; creams; gels; toners; sticks; sprays; ointments;cleansing liquid washes; cleansing solid bars; shampoos; hairconditioners; pastes; foams; powders; mousses; shaving creams; wipes;strips; patches (transdermal or non-transdermal); electrically-poweredpatches; wound dressing and adhesive bandages; hydrogels; film-formingproducts; facial and skin masks; and make-up such as foundations, eyeliners, and eye shadows.

(1) Sunscreens

Sunscreens used herein may be organic or inorganic. They include bothUVA and UVB protective ranges. Amounts of sunscreen may range from 0.01%to 20% by weight, 0.1% to 50% by weight, usually from 0.5% to 15% byweight, and often from 4% to 12% by weight of the cosmetic composition.

Organic sunscreens will have at least one chromophoric group absorbingwithin the ultraviolet ranging from 290 nm to 400 nm. Chromophoricorganic sunscreens may be divided into the following categories (withspecific examples) including: p-Aminobenzoic acid, its salts and itsderivatives (ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoicacid); Anthranilates (O-aminobenzoates; methyl, menthyl, phenyl, benzyl,phenylethyl, linalyl, terpinyl, and cyclohexenyl esters); Salicylates(octyl, amyl, phenyl, benzyl, menthyl, glyceryl, and dipropyleneglycolesters); Cinnamic acid derivatives (menthyl and benzyl esters,alpha-phenyl cinnamonitrile; butyl cinnamoyl pyruvate);Dihydroxycinnamic acid derivatives umbelliferone, methylumbelliferone,methylaceto-umbelliferone); Trihydroxycinnamic acid derivativesesculetin, methylesculetin, daphnetin, and the glucosides, esculin anddaphnin); Hydrocarbons (diphenylbutadiene, stilbene); Dibenzalacetoneand benzalacetophenone; Naphtholsulfonates (sodium salts of2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids);Dihydroxynaphthoic acid and its salts; o- andp-Hydroxybiphenyldisulfonates; Coumarin derivatives (7-hydroxy,7-methyl, 3-phenyl); Diazoles (2-acetyl-3-bromoindazole, phenylbenzoxazole, methyl naphthoxazole, various aryl benzothiazoles); Quininesalts (bisulfate, sulfate, chloride, oleate, and tannate); Quinolinederivatives (8-hydroxyquinoline salts, 2-phenylquinoline); Hydroxy- ormethoxy-substituted benzophenones; Uric and vilouric acids; Tannic acidand its derivatives (e.g., hexaethylether); (Butyl carbityl) (6-propylpiperonyl) ether; Hydroquinone; Benzophenones (Oxybenzone,Sulisobenzone, Dioxybenzone, Benzoresorcinol,2,2′,4,4′-Tetrahydroxybenzophenone,2,2′-Dihydroxy-4,4′-dimethoxybenzophenone); Octabenzone;4-Isopropyldibenzoylmethane; Butylmethoxydibenzoylmethane; Etocrylene;and 4-isopropyl-dibenzoylmethane).

Particularly important sunscreens are: 2-ethylhexyl p-methoxycinnamate(available as PARSOL MCX®), 4,4′-t-butyl methoxydibenzoylmethane (knowncommonly as Avobenzone, available as PARSOL 1789®), octylsalicylate(available as DERMABLOCK OS®), tetraphthalylidene dicamphor sulfonicacid (available as MEXORYL SX®), benzophenone-3 (Oxybenzone) andmixtures thereof.

Inorganic sunscreens are usually microfine particles of titanium dioxideand of zinc dioxide. “Microfine” is defined herein as average particlesize ranging from 10 nm to 200 nm, usually from 20 nm to 100 nm.

(2) Surfactants

Surfactants suitable for use may be those which can form emulsionsand/or association structures. Surfactants can be categorized as beingof the anionic, nonionic, cationic, or amphoteric type. The term“surfactants” are defined herein to include materials otherwise called“emulsifiers”.

The surfactants can be used at levels from 0.1% to 97% by weight,preferably from 2% to 75% by weight, 0.1% to 50% by weight, morepreferably from 10% to 90% by weight, and most preferably from 20% to70% by weight of the cosmetic composition.

Examples of surfactants which may be used in the compositions describedherein include salts of C8-C22 alkyl chain compounds. Representativesurfactants include sodium taliowate, sodium cocoate, sodium alkylsulfate (e.g., sodium lauryl sulfate and sodium myristyl sulfate),sodium N-acyl sarcosinates (e.g., sodium N-lauroyl sarcosinate andsodium N-myristoyl sarcosinate), sodium dodecylbenzenesulfonate, sodiumhydrogenated coconut fatty acid monoglyceride sulfate, sodium laurylsulfoacetate and N-acyl glutamates (e.g., N-palmitoyl glutamate),N-methylacyltaurin sodium salt, N-methylacyialanine sodium salt, sodiumalpha-olefin sulfonate and sodium dioctylsulfosuccinate;N-alkylaminoglycerols (e.g., N-lauryl-diamino-ethylglycerol andN-myristyldiaminoethyl glycerol), N-alkyl-N-carboxymethylammoniumbetaine and sodium 2-alkyl-1-hydroxyethylimidazoline betaine;polyoxyethylenealkyl ether, polyoxyethylene alkylaryl ether,polyoxyethylene lanolin alcohol, polyoxyethylene glyceryl monoaliphaticacid ester, polyoxyethylene sorbitol aliphatic acid ester,polyoxyethylene aliphatic acid ester, higher aliphatic acid glycerolester, sorbitan aliphatic acid ester, and polyoxyethylenesorbitanaliphatic acid esters such as polyoxyethylenesorbitan monooleate andpolyoxyethylene sorbitan monolaurate.

(3) Preservatives

Preservatives may be incorporated into the cosmetic compositions toprotect against the growth of potentially harmful microorganisms.Suitable traditional preservatives are alkyl esters ofpara-hydroxybenzoic acid. Other preservatives which have more recentlycome into use include hydantoin derivatives, propionate salts, and avariety of quaternary ammonium compounds. Cosmetic chemists are familiarwith appropriate preservatives and routinely choose them to satisfy thepreservative challenge test and to provide product stability.Particularly preferred preservatives are methylchloroisothiazolinone andmethylisothiazolinone combinations, phenoxyethanol, methyl paraben,propyl paraben, imidazolidinyl urea, sodium dehydroacetate and benzylalcohol. Preferred preservatives include phenoxyethanol,ethylhexylglycerine, or a combination thereof. Preservatives may beemployed in amounts ranging from 0.01% to 2% by weight of the cosmeticcomposition. Exemplary percent compositions of the preservative are0.01%, 0.1%, 0.9%, 1.0%, and 1.5%. In some forms, phenoxyethanolconstitutes 0.9% by weight, and ethylhexylglycerine constitutes 0.1% byweight of the composition.

(4) Desquamation Agents

Desquamation agents may be present. Illustrative are the monocarboxylicacids. Monocarboxylic acids may be substituted or unsubstituted with acarbon chain length of up to 16. Particularly preferred carboxylic acidsare the alpha-hydroxycarboxylic acids, beta-hydroxycarboxylic orpolyhydroxycarboxylic acids. The term “acid” is meant to include notonly the free acid but also salts and C1-C30 alkyl or aryl estersthereof and lactones generated from removal of water to form cyclic orlinear lactone structures. Representative acids are glycolic, lactic,malic and tartaric acids. A representative salt that is particularlypreferred is ammonium lactate. Salicylic acid is representative of thebeta-hydroxycarboxylic acids. Amounts of these materials when presentmay range from 0.1% to 50% by weight, 0.01 to 15% by weight of thecosmetic composition.

Preferred desquamation agents may be selected from the group consistingof glycolic acid, lactic acid, salicylic acid, retinoic acid, retinoland mixtures thereof, and including salt forms thereof.

(5) Antiperspirants

Antiperspirant skin care cosmetic compositions for use herein mayinclude well known antiperspirant metal salts of aluminum, zinc,zirconium and zirconium aluminum mixtures of sulfates, chlorides,chlorohydroxides, tetrachlorohydrex glycinates, alums, formates,lactates, benzyl sulfonates, succinates, phenol sulfonates and the like.Typical levels of antiperspirant metal salts range from 0.1% to 50% byweight, from 1% to 35%, preferably from 1.5% to 25% by weight of thecosmetic composition.

(6) Colorants

Colorants may either be dyes or pigments. A distinction is usually madebetween a pigment, which is insoluble in its vehicle (resulting in asuspension), and a dye, which either is itself a liquid or is soluble inits vehicle (resulting in a solution). A colorant can act as either apigment or a dye depending on the vehicle involved. In some cases, apigment can be manufactured from a dye by precipitating a soluble dyewith a metallic salt. The resulting pigment is called a lake pigment.

Among the more common dyes are Alizarin, Azophloxin, Chrysoidin, CongoRed, Fuchsin acid, Gentian violet, Janus green, Methyl Red, NaphtholGreen, Naphthol Yellow, Rose Bengal, Sudan II, Titan Yellow andcombinations thereof. Amongst pigments, titanium dioxide and aluminumlakes (aluminum salts of dyes) are most common. Amounts of the colorantmay, according to the type of cosmetic product (lipstick, foundation,hair dye, etc) range from 0.1% to 50% by weight, 0.01% to 10% by weight,usually from 0.01% to 5% by weight of the cosmetic composition.

(7) Cosmetically acceptable carrier

Cosmetic compositions of this invention also include a cosmeticallyacceptable carrier. Amounts of the carrier may range from 0.1% to 50% byweight, from 1% to 99.9% by weight, preferably from 70% to 95% byweight, most preferably from 80% to 90% by weight of the composition.Among the useful carriers are water, emollients, fatty acids, fattyalcohols, humectants, thickeners, hydrocarbons, and combinationsthereof. The carrier may be aqueous, anhydrous, or an emulsion.Preferably the compositions are aqueous, especially water and oilemulsions of the W/0 or 0/W, or double emulsion, such as the W/O/Wvariety.

Water when present as carrier or otherwise may advantageously beincorporated into the compositions as a deionized, sterilized orpasteurized liquid or can be heat treated or irradiated after havingbeen mixed with other components of the composition. These treatmentsinsure elimination of pathogenic microbes. Water, when present may be inamounts ranging from 5% to 95% by weight, 8% to 76% by weight, 20% to70% by weight, or 35 to 60% by weight of the composition. Exemplarypercent compositions of water include 9.6% by weight, 13.996% by weight,21.29% by weight, 21.29% by weight, 32.69% by weight, 60.64% by weight,71.11% by weight, and 75.05% by weight.

Emollient materials may serve as cosmetically acceptable carriers. Thesemay be in the form of silicone oils, synthetic or natural esters andhydrocarbons. Amounts of the emollients may range anywhere from 0.1% to95% by weight, from 0.1% to 50% by weight, preferably between 1% and 50%by weight, inclusive, from 1% to 25% by weight, of the cosmeticcomposition. A preferred emollient is caprylic/capric tryglyceride. Insome forms the capric/capric triglyceride constitutes about 15% byweight of the cosmetic composition.

Silicone oils may be divided into the volatile and nonvolatile variety.Volatile silicone oils are preferably chosen from cyclic(cyclomethicone) or linear polydimethylsiloxanes containing from 3 to 9,preferably from 4 to 5, silicon atoms.

Nonvolatile silicone oils useful as an emollient material includepolyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxanecopolymers. The essentially nonvolatile polyalkyl siloxanes usefulherein include, for example, polydimethyl siloxanes with viscosities offrom about 5×10⁻⁶ m²/s to 0.1 m²/s at 25° C. Among the preferrednonvolatile emollients useful in the present compositions are thepolydimethyl siloxanes having viscosities from about 1×10⁻⁵ m²/s toabout 4×10⁻¹ m²/s at 25° C.

Another class of nonvolatile silicones are emulsifying andnon-emulsifying silicone elastomers. Representative of this category isDimethicone/Vinyl Dimethicone Crosspolymer available as Dow Corning9040, General Electric SFE 839, and Shin-Etsu KSG-18. Silicone waxessuch as Silwax WS-L (Dimethicone Copolyol Laurate) may also be useful.

Among the ester emollients are: alkyl esters of saturated fatty acidshaving 10 to 24 carbon atoms. Examples thereof include behenylneopentanoate, isononyl isonanonoate, isopropyl myristate and octylstearate; ether-esters such as fatty acid esters of ethoxylatedsaturated fatty alcohols; polyhydric alcohol esters such as ethyleneglycol mono and di-fatty acid esters, diethylene glycol mono- anddi-fatty acid esters, polyethylene glycol (200-6000) mono- and di-fattyacid esters, propylene glycol mono- and di-fatty acid esters,polypropylene glycol 2000 monostearate, ethoxylated propylene glycolmonostearate, glyceryl mono- and di-fatty acid esters, polyglycerolpoly-fatty esters, ethoxylated glyceryl mono-stearate, 1,3-butyleneglycol monostearate, 1,3-butylene glycol distearate, polyoxyethylenepolyol fatty acid ester, sorbitan fatty acid esters, and polyoxyethylenesorbitan fatty acid esters are satisfactory polyhydric alcohol esters.Particularly useful are pentaerythritol, trimethylolpropane andneopentyl glycol esters of C₁-C₃₀ alcohols; wax esters such as beeswax,spermaceti wax and tribehenin wax; and sugar ester of fatty acids suchas sucrose polybehenate and sucrose polycottonseedate.

Hydrocarbons which are suitable cosmetically acceptable carriers includepetrolatum, mineral oil, C₁₁-C₁₃ isoparaffins, and especiallyisohexadecane, available commercially as Permethyl 101A from PresperseInc.

Fatty acids having from 10 to 30 carbon atoms may also be suitable ascosmetically acceptable carriers. Illustrative of this category arepelargonic, lauric, myristic, palmitic, stearic, isostearic, oleic,hydroxystearic and behenic acids.

Fatty alcohols having from 10 to 30 carbon atoms are another usefulcategory of cosmetically acceptable carrier. Illustrative of thiscategory are stearyl alcohol, lauryl alcohol, myristyl alcohol and cetylalcohol.

Humectants of the polyhydric alcohol-type can be employed ascosmetically acceptable carriers. Typical polyhydric alcohols includeglycerol (also known as glycerine), polyalkylene glycols and morepreferably alkylene polyols and their derivatives, including propyleneglycol, dipropylene glycol, polypropylene glycol, polyethylene glycoland derivatives thereof, sorbitol, hydroxypropyl sorbitol, hexyleneglycol, 1,3-butylene glycol, isoprene glycol, 1,2,6-hexanetriol,ethoxylated glycerol, propoxylated glycerol and mixtures thereof. Theamount of humectant may range anywhere from 0.1% to 50% by weight, 0.5%to 50% by weight, preferably between 1% and 15% by weight of thecomposition. In some forms the humectant constitutes about 15% by weightof the composition. In some forms, the humectant is glycerine.

Thickeners can be utilized as part of the cosmetically acceptablecarrier of compositions according to the present invention. Typicalthickeners include crosslinked acrylates (e.g. CARBOPOL 982®),hydrophobically-modified acrylates (e.g. CARBOPOL 13820), cellulosicderivatives and natural gums. Among useful cellulosic derivatives aresodium carboxymethylcellulose, hydroxypropyl methocellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose andhydroxymethyl cellulose. Natural gums suitable for the present inventioninclude guar, xanthan, sclerotium, carrageenan, pectin and combinationsof these gums. Inorganics may also be utilized as thickeners,particularly clays such as bentonites and hectorites, fumed silicas, andsilicates such as magnesium aluminum silicate (VEEGUM®). Amounts of thethickener may range from 0.1% to 50% by weight, 0.001% to 10% by weight,usually from 0.001% to 1% by weight, optimally from 0.01% to 0.5% byweight of the composition. Most preferred thickeners includehydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer,polyacrylate crosspolymer-6, or a combination thereof. Preferably, thethickeners include hydroxyethyl acrylate/sodium acryloyldimethyl tauratecopolymer, and polyacrylate crosspolymer-6. Preferably each of theseconstitutes about 0.5% by weight of the cosmetic composition.

(8) Additional Materials

Also included may be such materials as resveratrol, alpha-lipoic acid,ellagic acid, kinetin, retinoxytrimethylsilane (available from ClariantCorp. under the SILCARE 1M-75®), dehydroepiandrosterone (DHEA) andcombinations thereof. Ceramides (including Ceramide 1, Ceramide 3,Ceramide 3B, Ceramide 6 and Ceramide 7) as well as pseudoceramides areuseful. Amounts of these materials may range from 0.1% to 50% by weight,0.001 to 10% by weight, preferably from 0.01% to 1% by weight of thecomposition.

The cosmetic compositions may contain an active peptide selected frompentapeptides, derivatives of pentapeptides, and mixtures thereof. Asused herein, “pentapeptides” refers to both the naturally occurringpentapeptides and synthesized pentapeptides. A pentapeptidederivative-containing composition is MATRLXYL®, which is commerciallyavailable from Sederma, France. The pentapeptides and/or pentapeptidederivatives are preferably included in amounts of from 0.1% to 50% byweight, 0.001% to 20% wt/v.

The cosmetic compositions can include a skin lightening compound.Illustrative substances are placental extract, lactic acid, niacinamide,arbutin, kojic acid, ferulic acid, hydroquinone, resorcinol andderivatives including 4-substituted resorcinols and combinationsthereof. Amounts of these substances may range from 0.1% to 10% byweight, preferably from 0.5% to 2% by weight of the composition.

The cosmetic compositions may include vitamins. Illustrative vitaminsare Vitamin A (retinol), Vitamin B₂, Vitamin B₃ (niacinamide), VitaminB₆, Vitamin B12, Vitamin C, Vitamin D, Vitamin E, Vitamin K and Biotin.Derivatives of the vitamins may also be employed. For instance, VitaminC derivatives include ascorbyl tetraisopalmitate, magnesium ascorbylphosphate and ascorbyl glycoside. Derivatives of Vitamin E includetocopheryl acetate, tocopheryl palmitate and tocopheryl linoleate.DL-panthenol and derivatives may also be employed. A particularlysuitable Vitamin B₆ derivative is Pyridoxine Palmitate. Flavonoids mayalso be useful, particularly glucosyl hesperidin, rutin, and soyisoflavones (including genistein, daidzein, equol, and their glucosylderivatives) and mixtures thereof. Total amount of vitamins orflavonoids when present may range from 0.1% to 50% by weight, 0.001% to10% by weight of the composition.

In some forms, the cosmetic composition contains an emollient selectedfrom those described above; a thickening agent selected from thosedescribed above; water; a humectant selected from those described above;a preservative selected from those described above, and any of thequinones defined by Formula I, Formula II, Formula III.

In some forms, the cosmetic composition contains: caprylic/caprictryglyceride; hydroxyethyl acrylate/sodium acryloyldimethyl tauratecopolymer; polyacrylate crosspolymer-6; water; glycerin; phenoxyethanol;ethylhexylglycerin; and any of the quinones defined by Formula I,Formula II, or Formula III.

In some forms, the cosmetic composition contains: caprylic/caprictryglyceride, 15% by weight; hydroxyethyl acrylate/sodiumacryloyldimethyl taurate copolymer, 0.5% by weight; polyacrylatecrosspolymer-6, 0.5%, by weight; water, 77.75% by weight; glycerin, 5.0%by weight; phenoxyethanol, 0.9% by weight; ethylhexylglycerin, 0.1% byweight; and lapachol, 0.25% by weight.

In some forms, the cosmetic composition contains: caprylic/caprictryglyceride, 15% by weight; hydroxyethyl acrylate/sodiumacryloyldimethyl taurate copolymer, 0.5% by weight; polyacrylatecrosspolymer-6, 0.5%, by weight; water, 77.90% by weight; glycerin, 5.0%by weight; phenoxyethanol, 0.9% by weight; ethylhexylglycerin, 0.1% byweight; and myrtucommulone C, 0.1% by weight.

III. Methods of Using

The disclosed compositions can be used to inhibit CUL4 ubiquitin ligasein a subject in need thereof. For example the compositions can beadministered in conditions involving DNA damage and/or needing DNArepair, wound healing and/or skin dermatitis. In preferred embodiments,the cosmetic compositions can be used topically to treat the signs ofageing. These signs include formation of fine lines and wrinkles,inadequate skin firmness, reduction of skin luminescence, lack of skinsmoothness, poor skin elasticity, formation of age spots, blotching,sallowness, uneven pigmentation, spider veins (telangiectasia), thinningof hair, lack of hair lustre or shine, hair with split ends andcombinations thereof.

Advantageously, UV irradiated samples of the quinone or cosmeticcompositions formulated with the quinone exhibit, in testing against theCUL4 bio target, a reduction in DNA damage relative to a UV irradiatedcontrol of at least 10%, preferably at least 50%, most preferably by atleast 80% over baseline compared to no treatment control, as measured by% CPD (Cyclobutane Pyrimidine Dimer) formed in a test cell. Accordingly,the compositions should be used in DNA repair, particular in skin cells.

As shown herein, compounds in the disclosed compositions upregulategenes implicated in wound healing, tissue repair, improving collagendeposition at a site in need thereof, and inflammation, for example,inteleukin-6 (IL-6), fibroblast growth factor (FGF), GPHR, ADAM17, andVEGF. Accordingly, the disclosed formulations can improve the speed andefficiency of the healing process and/or decrease inflammation at a sitein need thereof. The compositions are applied are applied to a site inneed thereof, in an effective amount to upregulate expression of a geneselected from the group consisting of inteleukin-6 (IL-6), fibroblastgrowth factor (FGF), GPHR, ADAM17, and VEGF or downregulate expressionof Smad3. “Upregulated” or “downregulated” as used herein uses athreshold of 0.05 for statistical significance (p-value) and a log foldchange of expression with absolute value of at least 1 compared to notreatment control.

For example, IL-6 (the expression of w is upregulated by both RGN1518and RGN 1538) has direct, crucial role n proliferation and remodelingphases of wound healing (Lin, et al., J. Leukoc Biol., 73(6):713-21(2003), for example, by promoting collagen deposition and angiogenesis.Following damage of the epidermis, primary inflammatory cytokines likeTNFα and IL-1 are released and in turn, induce expression of IL-6.Primary inflammatory cytokines mediate inflammatory cell accumulation intissues, resulting in further damage. IL-6 counters this by inhibitingthe expression of primary inflammatory cytokines. IL-6 itself mediatesskin healing, and may promote the influx or differentiation ofanti-inflammatory macrophage populations that further promote repair.

The fibroblast growth factor (FGF) family contributes to the regulationof virtually all aspects of development and organogenesis, and afterbirth to tissue maintenance, as well as particular aspects of organismphysiology (Reviewed in Nunes, et al., Peer J. 4:e1535 (2016).

The Golgi pH regulator (GPHR) is an anion channel essential for normalacidification of the Golgi apparatus, and is therefore required for itsfunctions. GPHR is essential for the homeostasis of the epidermisincluding the formation of lamellar bodies and for the barrier function.Tarutani, et al., J Invest Dermatol., 132(8):2019-25 (2012).

ADAM17 (a disintegrin and metalloproteinase domain 17) axis plays a keyrole in skin barrier maintenance, inflammation and migration. Brooke, etal., Human Mol. Gen. 23(15):4064-4076 (2014).

VEGF (Vascular endothelial growth factor) stimulates wound healing viamultiple mechanisms including collagen deposition, angiogenesis andepithelization. In the clinical setting, the mitogenic, chemotactic, andpermeability effects of VEGF may potentially aid to promote repair innonhealing wounds in arterial occlusive disease and diabetes. It mayalso alleviate the “wound” of ischemic heart disease. Reviewed in Boa,et al., J. Surg. Res., 153(2):347-358 (2009).

The disclosed compositions can be used to downregulate genes, thedownregulation of which has been shown to be beneficial for woundhealing, for example, Smad3. Studies by Ashcroft et al. show thatabsence of Smad3 is associated with accelerated wound healing. Nat CellBiol. 1999 1(5):260-6. Smad3 (also known as Mothers againstdecapentaplegic homolog 3 Mothers against DPP homolog 3, Mad3, hMAD-3,JV15-2 car hSMAD3) is a transcriptional modulator activated by TGF-beta(transforming growth factor) and activin type 1 receptor kinase. Theseactivators exert diverse effects on a wide array of cellular processes.The Smad proteins mediate much of the signaling responses induced by theTGF-b superfamily. Briefly, activated type I receptor phosphorylatesreceptor-activated Smads (R-Smads) at their c-terminal two extremeserines in the SSXS motif, e.g. Smad2 and Smad3 proteins in the TGF-bpathway, or Smad1, Smad5 or Smad8 in the BMP pathway. Then thephosphorylated R-Smad translocated into nucleus, where they regulatetranscription of target genes. Based on microarray and animal modelexperiments, Smad3 accounts for at least 80% of all TGF-b-mediatedresponse.

Thus, in other embodiments, the compound can be applied topically toskin wounds to improve the speed and efficiency of the healing processin different types of wounds and inflammatory conditions of the skin,including, but not limited to cuts, burns, skin ulcers, sores,dermatitis etc or improve collagen deposition at a site in need thereof.There is also a need for better agents to heal diabetic wounds andwounds occurring in elderly people, which are both major problems. Thefeatures of the wound healing pathway also have overlap in anti-agingpathways, such as cell differentiation and migration. According, thecompounds disclosed herein could be applied to a subject with a diabeticwound and on wounds in the elderly. Studies by Lee et al., J.Immunotoxicol., 10(2):192-200 (2013) showed that IL-6 deficiencyexacerbates skin inflammation in a model of irritant dermatitis.Accordingly, upregulation of IL-6 production/expression can be usefulwithin the context of dermatitis.

Contact dermatitis is divided into two main manifestations, those ofallergic and irritant dermatitis. The major difference between the twopathologies is often described as whether the disease is ofimmunological origin (allergic), where T-cells are involved ornon-immunological origin (irritant), where physical damage is thought tobe the major initiating event. Dermatitis is generally characterized atthe histological level by neutrophil and macrophage infiltration and atthe molecular level by inflammatory cytokine production. The majordifference between the two types of contact dermatitis appears to be thesource of inflammatory cytokines. Whereas allergic dermatitis depends onT-cells, irritant type depends initially on dermal or epidermal cellsources. IL-6 is associated with both allergic and irritant dermatitis.In addition to its immunomodulatory activities, IL-6 is involved in thegrowth and differentiation of numerous cell types, including those ofdermal and epidermal origin. IL-6 treatment also appears to modulatestratum corneum regeneration and skin. barrier function. Lee et al., J.Immunotoxicol., 10(2):192-200 (2013), citations omitted)

Other uses for the presently described quinones are in cosmeticcompositions that remediate sunburn as after-care products, that controldiaper rash, that clear acne, that treat eczema, inhibit psoriasis,retard dandruff and control itching.

IV. Methods of Making

The cosmetic compositions can be formulated by creating an emulsioncontaining the components described above, using a cold processformulation method. Such emulsions can be made using cold processpolymeric, anionic, bases such as SEPIMAX ZEN®. In some forms, anemollient, such as caprylic/capric tryglyceride; a thickening agents,such as hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymerand polyacrylate crosspolymer-6; water; a humectant, such as glycerin;and preservatives, such as phenoxyethanol and ethylhexylglycerin can beused as base components in making the cosmetic compositions. Any of thequinones described above, can be added to the base components to makethe final cosmetic composition. Preferably, the quinones are lapachol,myrtucommulone C, thymoquinone, or a combination.

The cosmetic compositions may also be formulated using formulationmethods utilizing different temperatures. Preferably, any of thequinones described above can be added to the base components attemperatures from 0° C. to 50° C. by stirring the components until thequinones have solubilized in the formulation.

Except in the examples, or where otherwise explicitly indicated, allnumbers in this description indicating amounts of material or conditionsof reaction, physical properties of materials and/or use are to beunderstood as modified by the word “about” All amounts are by weight ofthe final cosmetic composition, unless otherwise specified.

It should be noted that in specifying any range of concentration oramount, any particular upper concentration can be associated with anyparticular lower concentration or amount.

For the avoidance of doubt, the word “comprising” is intended to mean“including” but not necessarily “consisting of” or “composed of.” Inother words, the listed steps or options need not be exhaustive.

The disclosure of the invention as found herein is to be considered tocover all embodiments as found in the claims as being multiply dependentupon each other irrespective of the fact that claims may be foundwithout multiple dependency or redundancy.

EXAMPLES Example 1. Screen for Active Ingredients Derived from NaturalSources that have the Ability to Inhibit the Activity of a TargetProtein, Cullin 4A CUL4A Methods

A two-tiered approach was employed to discover novel active ingredientsderived from natural sources that have the ability to inhibit theactivity of a target protein, cullin 4A CUL4A, and which can be used incosmetic compositions.

The first tier used an in silico screen and comprehensive computeralgorithm to screen a library of over ˜150,000 natural products thathave the ability to inhibit CUL4A based on their structure and predictedability to bind to the CUL4A protein and disrupt its activity.

The second tier of screening involved experiments that coveredmodulating the activity of CUL4A. The top compounds with predictedactivity from the first tier were subjected to tests to identify whichactives have significant inhibitory activity against CUL4A.

Results

In silico screening of the ˜150,000 compounds resulted in a hit rate ofapproximately 0.36% or 54 active ingredients that passed setcomprehensive filters with a high (<88%) predictive inhibitory activityagainst CUL4A. A BPB-CUL4A AlphaLISA assay was performed using the 54compounds to determine their CUL4A inhibitory properties in vitro. Next,these 54 leads were tested for their cell-based inhibitory activityagainst CUL4A. A first cell-based assay involved the inhibition of DNAdamage-binding protein 2 (DDB2) degradation in mouse embryonicfibroblast (MEF) cells in vitro. To determine the specificity of thecompounds, another cell-based assay was performed to determine theinhibition of IKBa degradation in HeLa cells in vitro. Preferably, thecompounds show high DDB2 inhibition and less inhibition of IKBadegradation. IkBa is a target of CUL4B, and this assay provides insightinto the specificity of the compounds. These tests led to the selectionof three active compounds that passed inhibition and selectivitythresholds and, thus, were suitable for use in cosmetic compositions.These were thymoquinone, lapachol and myrtucommulone C.

Predictive activity against CUL4A was scored from 0-1, with 1 being thehighest predictive activity. Outlined below are the results of the insilico predictions.

In Silico Average Predicted Activity

Compound Ave. Predicted Activity Thymoquinone 0.936 Lapachol 0.910Myrtucommulone C 0.895The Table below reports the ability of compounds to disrupt CUL4Aactivity in vitro (in a cell free CUL4 inhibition assay) ascertainedfrom the BPB-CUL4A AlphaLISA assay. Activity above 30% was set todistinguish true hits from false positives.

In Vitro Inhibition Results

Compound % Inhibitory Activity Thymoquinone 70.4% Lapachol 34.4%Myrtucommulone C 48.9%In a further Table below are reported in vitro cell based resultsdisplayed as a percentage increased inhibition of CUL4A over baselinecompared to a no treatment control i.e., DMSO.

In Vitro Cell Based Assay

Compound % Inhibit Thymoquinone 85% Lapachol 80% Myrtucommulone C 115%

In this cell-based assay, the % is DDB2 (DNA binding degradation protein2) remaining after UV treatment over baseline compared to a controlgroup. In the DMSO control group, the DDB2 remaining % was between20-30%.

Lastly, tests were conducted on human skin cells. The testing wasperformed using neonatal foreskin keratinocytes, a type of skin cellthat is a common model for skin testing across the cosmetic industry.The skin cells were purchased from Thermo Fisher Scientific Co. (NY) andgrown in Dulbecco Modified Eagle Medium (DMEM) supplemented with 10%Fetal Bovine Serum (Thermo Fisher Scientific). Cultures were maintainedat 37° C. within an air atmosphere of 5% carbon dioxide and about 95%humidity.

The skin cells were seeded in 12-well plates and incubated for 24 hours.After incubation, the cells were washed in phenyl benzene sulfonate(PBS) and irradiated with UVB at a dosage of 35 mJ/cm² using a ViberLourmat BIO-Sun System (Marne-la-Vallee, France). The test compounds andcontrol materials were added to the medium immediately following UVBirradiation; the treated mediums were allowed to continue for 12 hoursat 37° C. under the air atmosphere with 5% carbon dioxide at about 95%humidity. In parallel, each test compound was added to non-irradiatedcells as baseline controls. Untreated cells were used as negativecontrols. All treatments were performed in triplicate. Dosage levels forsamples were 12.5 microMolar except lapachol dosed at 3 microMolar.Following incubation, the cells were washed with PBS, collected andstored at −80° C.

DNA was extracted from the collected cells using a QIAamp Blood Kit(QIAGEN, CA, USA) in accordance with the manufacturer's protocol. Theamounts of cyclobutane pyrimidine dimers (CPDs) in the various sampleswere determined by the CPD ELISA protocol. In accordance with thisprotocol, an OXISELECT® UV-Induced DNA Damage ELISA Kit (Cell BiolabsInc., CA, USA) was employed for the testing done in accordance with themanufacturer's instructions. Amounts of CPD in UVB-treated samples weredetermined in percentage relative to the value of untreated fibroblasts.The greater the measured % CPD, the greater the DNA damage. Thus, in theTable below, the smaller the “Avg (% Untreated)” value, the better isthe UVB damage induced inhibitory effect.

Mean standard deviation comparisons between data groups employed theGraphPad Prism 6.05 software (GraphPad Software, CA, USA). Statisticalanalysis was performed using ANOVA with Holm-Sidak's test or unpairedt-test with Welch's correction.

Results of the human fibroblast cell assay are recorded in the Tablebelow. Therein is shown the significant DNA damage inhibitory effect oflapachol, thymoquinone and myrtucommulone C, with the latter being themost effective inhibitor.

Human Fibroblast Cell Assay

Test Sample or Control Avg (% Untreated) St Dev Untreated Control (noUVB) 99.2 12.59 Untreated Control (UVB) 3907 423.1 Niacinamide 2216 64.4Lapachol 2076 127.2 Thymoquinone 2554 252 Myrtucommulone C 1362 307.8

In summary, the activity of the compounds has been tested in threedifferent phases: the computer screen, an in vitro assay designed tospecifically detect CUL4A inhibition, and also lastly in a biologicalsetting having activity in cells.

Example 2. Formulation for a Skin Care Product Including Thymoquinone

An illustrative skin care product including thymoquinone for treatingage spots and lightening skin has the formula below.

Component Weight % Thymoquinone 0.10 Niacinamide 4.00 Isohexadecane 3.00Isopropyl isostearate 2.00 Sucrose Polycottonseedate 0.70Polymethylsilsesquioxane 0.25 Cetearyl Glucoside/Cetearyl Alcohol 0.25Behenyl Alcohol 0.40 Ethyl Paraben 0.20 Propyl Paraben 0.10 CetylAlcohol 0.30 Stearyl Alcohol 0.45 PEG-100 Stearate 0.10 Glycerin 8.50Titanium Dioxide 0.60 Polymethacrylate 2.00 Dimethicone/Dimethiconol2.00 Water to 100

The water phase components are combined in a suitable vessel and heatedto 75° C. In a separate suitable vessel, combine the oil phaseingredients and heat to 75″ C. Next add the oil phase to the water phaseand mill the resulting emulsion (e.g., with a Tekmar™ T-25 mill). Then,add the thickener to the emulsion and cool the emulsion to 45° C. whilestirring. At 45° C., add the remaining components. Cool the product andstir to 30° C. and pour into suitable containers.

Example 3. Representation a Skin Care Product Including Lapachol

A representative skin care composition incorporating Lapachol in theform of a cosmetic lotion is outlined below:

Component Weight % Water Balance Disodium EDTA 0.05 Methyl Paraben 0.15Magnesium Aluminum Silicate 0.60 Triethanolamine 1.20 Xanthan Gum 0.20Natrosol ® 250HHR (ethyl cellulose) 0.50 Butylene Glycol 3.00 Glycerin2.00 Sodium Stearoyl Lactylate 0.10 Glycerol Monostearate 1.50 StearylAlcohol 1.50 Isostearyl Palmitate 3.00 Silicone Fluid 1.00 Lapachol 0.25Butylated Hydroxy Toluene 0.05 Vitamin E Acetate 0.01 PEG-100 Stearate2.00 Stearic Acid 3.00 Propyl Paraben 0.10 Parsol MCX ® 2.00Caprylic/Capric Triglyceride 0.50 Hydroxycaprylic Acid 0.01

Component Weight % C12-15 Alkyl Octanoate 3.00 (Isotridecyloxy)propionicacid (branched) 2.00 or (Isotridecyloxy)acetic acid (branched) Vitamin APalmitate 0.10 Bisabolol 0.01 Vitamin A Acetate 0.01 Fragrance (20%Limonene and 3% gamma 0.03 terpinene) Retinol 50C 0.02

Example 4. Make-Up Product Including Lapachol

A water-in-oil topical liquid make-up foundation incorporating Lapacholis described below.

Component Weight % Lapachol 2.00 Cyclomethicone 9.25 Oleyl Oleate 2.00Dimethicone Copolyol 20.00 Talc 3.38 Pigment (Iron Oxides) 10.51 SpheronL-1500 (Silica) 0.50 Synthetic Wax 0.10 Arachidyl Behenate 0.30Cyclomethicone 1.00 Trihydroxystearin 0.30 Laureth-7 0.50 Propyl Paraben0.25 Perfume 0.10 Methyl Paraben 0.12 Propylene Glycol 8.00 Niacinamide4.00 Glycerin 3.00 Sodium Chloride 2.00 Water To 100

Example 5. Myrtucommulone C-Containing Foaming Cleaner

An aerosol packaged foaming cleanser is outlined fortified withmyrtucommulone C.

Component Weight % Sunflower Seed Oil 10.00 Glycerin 10.00 MaleatedSoybean Oil 5.00 Silicone Urethane 1.00 Polyglycero-4 Oleate 1.00 SodiumC14-16 Olefin Sulfonate 15.00 Sodium Lauryl Ether Sulphate (25% active)15.00 Cocoamidopropylbetaine 15.00 DC 1784 ® (Silicone Emulsion 50%)5.00 Polyquaternium-11 1.00 Myrtucommulone C 0.01 Fragrance (20%Limonene) 0.70 Water To 100

Example 6. Illustrative Toilet Bar Formula Incorporating Lapachol

Component for an illustrative toilet bar formula incorporating Lapacholis listed below.

Component Weight % Sodium Soap (85/15 Tallow/Coconut) 77.77 Inventivecompound 5a 3.50 Dimethicone 2.00 Sodium Chloride 0.77 Titanium Dioxide0.40 Ethylene Brassylate 1.50 Disodium EDTA 0.02 Sodium Etidronate 0.02Lapachol 0.024 Water To 100

Example 7. Shampoo Incorporating Thymoquinone

A shampoo composition with thymoquinone is described below forillustrative purposes.

Component Weight % Ammonium Laureth Sulfate 12.00 Ammonium LaurylSulfate 2.00 Cocoamidopropyl Betaine 2.00 Sodium Lauroamphoacetate 2.00Glycerin 12.00 Thymoquinone 1.50 Ethylene Glycol Distearate 1.50Cocomonoethanolamide 0.80 Cetyl Alcohol 0.60 Polyquaternium-10 0.50Dimethicone 1.00 Zinc Pyridinethione 1.00 Sodium Citrate 0.40 CitricAcid 0.39 Sodium Xylene Sulfonate 1.00 Fragrance (10% Limonene) 0.40Sodium Benzoate 0.25 Kathon CG ® 0.0008 Benzyl Alcohol 0.0225 Water To100

Example 8. Antiperspirant Formulation Incorporating Thymoquinone andLapachol

This Example illustrates an antiperspirant formula incorporatingthymoquinone and lapachol in combination.

Component Weight % (Isotridecyloxy)propionic acid (branched) 2.0Cyclopentasiloxane 37.0 Dimethicone 20.0 Aluminum ZirconiumTrichlorohydrex Glycinate 15.0 Thymoquinone and Lapachol (1:1 wt ratio)5.0 C₁₈-C₃₆ Acid Triglyceride 5.0 Microcrystalline Wax 3.0 Glycerin 8.0Silica 2.5 Dimethicone Crosspolymer 1.0 Ethylene Brassylate 0.5 DisodiumEDTA 0.4 Butylated Hydroxytoluene 0.3 Citric Acid 0.3

Example 9. Myrtucommulone C-Containing Formulation for Sunburn Treatment

This example describes a sunburn treatment composition including the DNArepair quinone which is myrtucommulone C.

Component Weight % Cocoa Butter 30.0 Shea Butter 18.0 Jojoba Oil 15.5Petrolatum 15.0 Stearic Acid 6.0 Magnesium Sulphate Pentahydrate 3.0Zinc Oxide 1.9 Myrtucommulone C 1.0 Water to 100

Example 10. Stability Studies for RGN 1538 (Lapacol Composition) and RGN1518 (Myrtucommulone C Composition)

Two cosmetic compositions were prepared, one containing lapachol(denoted RGN 1538) and the other containing myrtucommulone C (denotedRGN 1518) as active ingredients, and the stabilities of the activeingredients in these compositions were evaluated.

% Change % of Sample Name RGN 1538 Specification Actual Differenceoriginal Time 0 (Mar. 16, 2017) 0.25 0.25 0% 100% RT 2 Weeks 0.25 0.21315% 85% 40° C., 2 weeks 0.25 0.243 3% 97% 50° C., 2 weeks 0.25 0.251 0%100% −5° C., 2 weeks 0.25 0.252 −1% 101% F/T, 2 week 0.25 0.21 16% 84%RT, 4 Weeks 0.25 0.198 21% 79% 40° C., 4 weeks 0.25 0.25 0% 100% 50° C.,4 weeks 0.25 0.25 0% 100% −5° C., 2 weeks 0.25 0.252 −1% 101% Cycle 3X0.25 0.183 27% 73% RT, 6 Weeks 0.25 0.178 29% 71% 40° C., 6 weeks 0.250.252 −1% 101% −5° C., 6 weeks 0.25 0.252 −1% 101% RT, 8 Weeks 0.250.178 29% 71% 40° C., 8 weeks 0.25 0.252 −1% 101% −5° C., 8 weeks 0.250.249 0% 100% RT, 12 Weeks 0.25 0.146 42% 58% 40° C., 12 weeks 0.250.254 −2% 102% −5° C., 12 weeks 0.25 0.251 0% 100%

The components of the RGN1538 compositions were as follows:caprylic/capric tryglyceride, 15% by weight; hydroxyethylacrylate/sodium acryloyldimethyl taurate copolymer, 0.5% by weight;polyacrylate crosspolymer-6, 0.5%, by weight; water, 77.75% by weight;glycerin, 5.0% by weight; phenoxyethanol, 0.9% by weight;ethylhexylglycerin, 0.1% by weight; and RGN1538, 0.25% by weight.

% Change % of Sample Name RGN 1518 Specification Actual Differenceoriginal Time 0 (Mar. 17, 2017) 0.096 0.091 5% 95% RT, 2 Weeks 0.0960.089 7% 93% 40° C., 2 weeks 0.096 0.088 8% 92% 50° C., 2 weeks 0.0960.089 7% 93% −5° C., 2 weeks 0.096 0.087 9% 91% F/T, 2 week 0.096 0.0924% 96% RT, 4 Weeks 0.096 0.087 9% 91% 40° C., 4 weeks 0.096 0.088 8% 92%50° C., 4 weeks 0.096 0.092 4% 96% −5° C., 2 weeks 0.096 0.088 8% 92%Cycle 3X 0.096 0.091 5% 95% RT, 6 Weeks 0.096 0.09 6% 94% 40° C., 6weeks 0.096 0.089 7% 93% −5° C., 6 weeks 0.096 0.087 9% 91% RT, 8 Weeks0.096 0.088 8% 92% 40° C., 8 weeks 0.096 0.088 8% 92% −5° C., 8 weeks0.096 0.092 4% 96% RT, 12 Weeks 0.096 0.096 0% 100% 40° C., 12 weeks0.096 0.098 −2% 102% −5° C., 12 weeks 0.096 0.095 1% 99%

The components of the RGN1518 compositions were as follows:caprylic/capric tryglyceride, 15% by weight; hydroxyethylacrylate/sodium acryloyldimethyl taurate copolymer, 0.5% by weight;polyacrylate crosspolymer-6, 0.5%, by weight; water, 77.90% by weight;glycerin, 5.0% by weight; phenoxyethanol, 0.9% by weight;ethylhexylglycerin, 0.1% by weight; and RGN1518, 0.1% by weight.

Acceptable degradation of active compounds at the acceleratedtemperature conditions (40° C., 50° C., −5° C.) is 20% or 80% oforiginal. The compounds RGN1518 and RGN1538 met this criteria at thesetemperatures at the two-, four-, six-, eight-, and 12-week time points.

Results from these tests show that the active ingredient is stable overa period of twelve weeks at varying accelerated temperature conditions.Thus, active ingredients should remain in the formulation and notbreakdown.

Example 11. Insult Patch Tests for RGN1518 and RGN1538

Lastly a repeat insult patch test (RIPT) was performed using the twocosmetic compositions described above. About fifty human volunteers wereinvolved for each cosmetic composition (50 for RGN1518 and 52 forRGN1538).

Methods

Fifty-seven subjects, male and female, ranging in age from 20 to 75years were selected to evaluate each cosmetic composition. Fifty-twosubjects completed the study in each case. The remaining subjectsdiscontinued their participation for various reasons, which wereunrelated to the application of the test material.

(i) Inclusion Criteria

The following criteria were used to include subjects in the tests:

a. Male and female subjects, age 16^(a) to 79 years.

b. Absence of any visible skin disease which might be confused with askin reaction from the test material.

c. Prohibition of use of topical or systemic steroids and/orantihistamines for at least seven days prior to study initiation.

d. Completion of a medical history form and the understanding andsigning of an Informed Consent form.

e. Considered reliable and capable of following directions. ^(a)Withparental or guardian consent

(ii) Exclusion Criteria

a. Ill-health.

b. Under a doctor's care or taking medication(s) which could influencethe outcome of the study.

c. Females who are pregnant or nursing.

d. A history of adverse reactions to cosmetics or other personal careproducts.

The upper back between the scapulae served as the treatment area.Approximately 0.2 g of the test material, or an amount sufficient tocover the contact surface, was applied to a 1″×1″ absorbent pad portionof a clear adhesive dressing. This was then applied to the appropriatetreatment site to form a semi-occlusive patch.

(iii) Induction Phase

Patches were applied three (3) times per week (e.g., Monday, Wednesday,and Friday) for a total of nine (9) applications. The site was marked toensure the continuity of patch application. Following supervised removaland scoring of the first Induction patch, participants were instructedto remove all subsequent Induction patches at home, twenty-four hoursafter application. The evaluation of this site was made again just priorto re-application. If a participant was unable to report for an assignedtest day, one (1) makeup day was permitted. This day was added to theInduction period.

(iv) Induction Phase

With the exception of the first supervised Induction Patch reading, ifany test site exhibited a moderate (2-level) reaction during theInduction Phase, application was moved to an adjacent area. Applicationswere discontinued for the remainder of this test phase, if a moderate(2-level) reaction was observed on this new test site. Applicationswould also be discontinued if marked (3-level) or severe (4-level)reactivity was noted.

Rest periods entailed one day following each Tuesday and Thursdayremoval, and two days following each Saturday removal.

(v) Challenge Phase

Approximately two (2) weeks after the final induction patch application,a challenge patch was applied to a virgin test site adjacent to theoriginal Induction patch site, following the same procedure describedfor Induction. The patch was removed and the site scored at the clinicDay 1 and Day 3 post-application.

The formation of erythema and/or additional dermal sequelae were thecriteria for evaluating the performance of the cosmetic compositions.Erythema was scored numerically according to the key below. If present,additional dermal sequelae were indicated by the appropriate letter codeand a numerical value for severity.

Number Meaning Letter(s) Meaning 0 No visible skin reaction E Edema 0.5Barely perceptible D Dryness 1 Mild S Staining 2 Moderate P Papules 3Marked V Vesicles 4 Severe B Bullae U Ulceration Sp Spreading

Results

There were no adverse events, amendments, or deviations. The resultsfrom the tests showed that the active ingredients do not cause any skinirritation or dermal sensitization on human subjects.

While the present compositions and methods have been described withreference to the specific variations thereof, t should be understood bythose skilled in the art that various changes may be made andequivalents may be substituted without departing from the true spiritand scope of the compositions and methods described herein. In addition,many modifications may be made to adapt a particular situation,material, composition of matter, process, process step or steps, to theobjective, spirit and scope of the compounds and methods describedherein. All patents and publications cited above are hereby incorporatedby reference.

Example 12: Chemical Analysis of a Natural Isolate of Myrtucommulone Cand Samples of Synthetic Myrtucommulone C

Myrtucommulone C isolated from a natural source, (the Myrtus communisplant) and samples of synthetic Myrtucommulone C were used in thisanalysis. Samples were analyzed by ¹H and ¹³C NMR spectroscopy and analmost complete chemical shift assignment of the first synthetic samplewas performed using 2-dimensional NMR spectroscopy (TOCSY, HSQC, HMBCand ROESY). These analysis revealed the following:

The isolated and synthetic samples contain the same primary components,which are diastereomers and have the structures below:

However, the proportion of the diastereomers differed between thesamples.

The isolated natural sample contained ˜65% MyrtC as an 88% to 12%mixture of diastereomers.

The NMR analysis could not unambiguously determine which diastereomerwas in excess, but, the major component was assigned as R*,R*-MyrtCbased on the stereochemistry of the closely related natural productsR*,R*-Myrtucommulone-D and R*,R*-Myrtucommulone-E for which X-raycrystal structures have been reported in the literature (Shaheen, etal., “New α-Glucosidase Inhibitors and Antibacterial Compounds fromMyrtus communis L. Eur. J. Org. Chem., 2 2371-2377 (2006)).

By contrast the first synthetic sample contained ˜98% MyrtC as a 42% to58% mixture of diastereomers. The major diastereomer in this sample wasthe same as the minor one in the isolated sample.

The second synthetic sample contained ˜95% MyrtC as a 50% to 50% mixtureof diastereomers.

Each diastereomer exists as a pair of rotomers, which exchange on theseconds time-scale at ambient temperature:

The samples did not contain the tautomeric structures below:

The observed spectroscopic data did not match the data reported for thenatural product in the literature by Shaheen, et al., Eur. J. Org.Chem., 2 2371-2377 (2006).

Example 13: Microarray Analysis of Differential Gene Expression in HumanEpidermal Keratinocytes and Fibroblasts Following Treatment with RGN1518(Containing Myrtucommolone C) and RGN1538 (Containing Lapachol)

A study was conducted to evaluate the differential gene expression inadult human epidermal keratinocytes and fibroblasts after treatment withcompounds RGN1518 and RGN1538.

Materials and Methods

(i) Compounds Tested

RGN1518 (M, Repairogen): stock solution in DMSO; tested at 3.1 μM and1.6 μM final concentrations. RGN1538 (L, Repairogen): stock solution inDMSO; tested at 62 μM and 31 μM final concentrations. Niacinamide (N,35318 SE, Making Cosmetics, WA, USA): stock solution in DMEM; tested at50 mM final concentration. Niacinamide was used as a positive control.

(ii) Cell Culture

Normal primary adult human keratinocytes derived from a 29-year-olddonor were purchased from PromoCell (Heidelberg, Germany) and culturedin keratinocytes growth medium (Epilife+EDGS, Thermo Fisher Scientific,NY, USA). Keratinocytes cultures were maintained at 37° C. with 5% CO₂and ˜95% humidity.

Normal human dermal adult fibroblasts derived from a 35-year-old donorof were purchased from CELLnTec (Bern, Switzerland) and grown in DMEMsupplemented with 10% FBS (Life Technologies, CA, USA). Fibroblastscultures were maintained at 37° C. with 5% CO₂ and ˜95% humidity.

(iii) Cytotoxicity Assay

Cytotoxicity was evaluated using the Cell Titer96 Aqueous One (Promega,WI, USA) basic test according to manufacturer's instructions. Cells wereseeded at a density of 10,000 cells/well in a 96-well plate and culturedovernight. Treatments with seven doses of compounds were carried out for24 hours, in triplicates. Colorimetric analysis was performed using anabsorbance of 490 nm. Inhibition of viability of more than 20% of thecontrol values was considered cytotoxic.

(iv) Treatments in Cultured Human Keratinocytes and Fibroblasts

Normal primary human keratinocytes were seeded in 6-well plates andincubated for 24 h. Cells were then washed in PBS (Thermo FisherScientific) and reincubated for 24 more hours in the presence of RGN1518and RGN1538 (each at two different concentrations), vehicle control, orpositive control. Following treatment, the cells were washed with PBS,collected and stored frozen at −80° C. before RNA extraction.

Normal primary human fibroblasts were seeded in 6-well plates andincubated for 24 h. After incubation, cells were washed in PBS (ThermoFisher Scientific) and treated for 24 hours with RGN1518 and RGN1538,each at two concentrations, vehicle control, or positive control.Following incubation, the cells were washed with PBS, collected andstored frozen at −80° C. before RNA extraction.

(v) RNA Extraction

RNA was extracted using a Qiagen RNeasy kit (Qiagen, CA, USA) accordingto manufacturer's protocol.

(vi) Quality Control of Total RNA

RNA Integrity testing was performed by Advanced BioMedical Laboratories(Cinnaminson, N.J.) to confirm the integrity and overall quality oftotal RNA samples. A proprietary algorithm that takes several QCparameters into account (e.g. 28S/18S peak area ratios, unexpected peaksin the 5S region, etc.) was used to calculate the RNA Integrity Number(RIN). A RIN number of 10 indicates perfect RNA quality; a RIN number of1 indicates degraded RNA. According to published data and our ownexperience, RNA with a RIN number >8 is of sufficient quality for geneexpression profiling experiments. RIN number for all RNA samples was >8.

(vii) Microarray Analysis

18 vials containing RNA isolated from human epidermal keratinocytes and18 vials containing RNA isolated from human fibroblasts were shipped toThermo Fisher Scientific, Advanced BioMedical Laboratories (Cinnaminson,N.J.) on dry ice for Affymetrix Human Clariom D array processing.

(viii) Statistics

The differential gene expression was obtained using a threshold of 0.05for statistical significance (p-value) and a log fold change ofexpression with absolute value of at least 1. Gene expression wasfurther analysed using Differential Expression Analysis and PathwayAnalysis iPathwayGuide) by Advaita Bioinformatics Services (Plymouth,Mich.) in the context of pathways obtained from the Kyoto Encyclopediaof Genes and Genomes (KEGG) database (Release 84.0+/10-26, October 17)(Kanehisa et al., 2000; Kanehisa et al., 2002), gene ontologies from theGene Ontology Consortium database (2017 Nov. 6) (Ashburner et al., 2000;Gene Ontology Consortium, 2001), miRNAs from the miRBase (Release 21)and TARGETSCAN (Targetscan version:Mouse:7.1, Human:7.1) databases(Agarwal et al., 2015; Nam et al., 2014; Griffiths-Jones et al., 2008;Kozomara and Griffiths-Jones, 2014; Friedman et al., 2009; Grimson etal., 2007), and diseases from the KEGG database (Release 84.0+/10-26,October 17) (Kanehisa et al., 2000; Kanehisa et al., 2002). Allreferences are available in the reports for bioinformatics analysis ofdifferential gene expression provided by Advaita Bioinformatics Servicesat the following link.

Results

(i) Cytotoxicity Analysis

The cytotoxicity assay on primary human keratinocytes from adult donorwas performed after 24 h of culture in the presence of differentconcentrations of each compound, as indicated in FIG. 2A and Table 1.

TABLE 1 Cytotoxicity of different concentrations of RGN1538 and RGN1518on human keratinocytes. Avg (% of untreated) StDev Untreated 100%8.056481717 DMSO 101% 2.725249072 RGN1538 62.25 μM 84% 1.889771785RGN1538 31.1 μM 86% 7.802238332 RGN1538 15.5 μM 86% 2.487424853 RGN1518400 μM 51% 3.565711372 RGN1518 200 μM 54% 1.806391994 RGN1518 100 μM 43%1.628751471 RGN1518 50 μM 47% 2.256623011 RGN1518 24.8 μM 43%1.313815574 RGN1518 12.4 μM 44% 2.650997535 RGN1518 6.2 μM 80%2.700414723 Niacinamide 200 mM 46% 1.072141839 Niacinamide 100 mM 58%1.660948138 Niacinamide 50 mM 95% 1.660948138 Niacinamide 25 mM 108%2.737443434 Niacinamide 12.5 mM 104% 1.887299247 Niacinamide 6.2 mM 106%6.728390986 Niacinamide 3.1 mM 105% 3.695979563

Higher concentrations of RGN1538 (125 μM, 252 μM, 500 μM and 1000 μM)showed interference in the cell viability studies (data not shown).

RGN1538 at concentrations up to 62.25 μM, RGN1518 at concentrations upto 6.2, and Niacinamide at concentrations up to 50 mM showed nocytotoxicity on cultured primary human keratinocytes (FIG. 2). CompoundRGN1538 at concentrations higher than 62.25 μM shows interference withthe assay which is masking the toxicity effect. Based on thecytotoxicity experiments, the highest non-toxic concentrations wereselected for the Microarray Analysis.

The cytotoxicity assay on primary human fibroblasts from adult donor wasperformed after 24 h of culture in the presence of differentconcentrations of each compound, as indicated in FIG. 2B and Table 2.

TABLE 2 Cytotoxicity of different concentrations of RGN1538 and RGN1518on Fibroblasts Avg (% of untreated) StDev Untreated 100% 0.978921 DMSO99% 2.715211 RGN1538 62.25 μM 100% 56.41252 RGN1538 31.1 μM 98% 0.67824RGN1538 15.5 μM 99% 6.550097 RGN1518 400 μM 54% 5.251461 RGN1518 200 μM72% 10.43805 RGN1518 100 μM 74% 10.97012 RGN1518 50 μM 88% 7.78021RGN1518 24.8 μM 90% 6.135177 RGN1518 12.4 μM 94% 2.049005 RGN1518 6.2 μM97% 0.635915 Niacinamide 200 mM 61% 3.813726 Niacinamide 100 mM 89%2.436398 Niacinamide 50 mM 91% 1.217468 Niacinamide 25 mM 100% 0.375769Niacinamide 12.5 mM 97% 1.540407 Niacinamide 6.2 mM 99% 5.916572Niacinamide 3.1 mM 100% 7.955808

Higher concentrations of RGN1538 (125 μM, 252 μM, 500 μM and 1000 μM)showed interference in the cell viability studies (data not shown).

RGN1518 at concentrations up to 50 RGN1538 at concentrations up to 62.25and Niacinamide at concentrations up to 100 mM showed no cytotoxicity oncultured primary human fibroblasts (FIG. 2B). Compound RGN1538 atconcentrations higher than 62.25 μM shows interference with the assaywhich is masking the toxicity effect.

Microarray Analysis Treatment with Testing Compounds

Effect of Compound RGN1538 on Primary Keratinocyte Gene Expression

The effect of Compound RGN1538 on gene expression in culturedkeratinocytes was analyzed by microarray and bioinformatics analysis.RGN1538 at concentrations of 31 μM upregulated 250 genes anddownregulated 556 were downregulated genes, out of the total of 24905assessed genes. At concentration of 62 μM, RGN1538 upregulated 258 genesand downregulated 461 genes. Genes were identified as being“upregulated” or “downregulated” using a threshold of 0.05 forstatistical significance (p-value) and a log fold change of expressionwith absolute value of at least 1. RGN1538 induced differential geneexpression in Metabolism of Xenobiotics by Cytochrome P450 and SteroidHormone Biosynthesis Pathways, while positive control Niacinamide had nomajor effect on these pathways.

RGN1538 upregulated genes involved in phase-I detoxification and steroidhormone biosynthesis: cytochrome P450 isoforms CYP1A1, CYP1B1, CYP2BG;glutathione S-transferase GSTM3; and aldo-keto-reductases, AKR1C1,AKR1C2, AKR1C3 and AKR1B15.

RGN1538 downregulated genes involved Cell Cycle Pathway: MAD2L1; CDC20;cyclins CCNE2, CCNA2, CCNB2, and CCNB1; and serine/threonine kinaseBUB1; PLK1; CDC25C; BUB1B; TTK; ORC1; MCM6; MAD2L1.

RGN1538 upregulated some genes, associated with inflammation: IL6;cytokine receptors IL1R2, IL2RG and IL1RL1 (Interleukin 1 receptor-like1). IL1R11 is a member of the interleukin 1 receptor family.Importantly, positive control Niacinamide had no effect on IL1RG, andthe IL1R2 cytokine receptor, and only upregulated IL6 and IL1RL1receptor.

Interleukin 6 (IL-6) is an interleukin that acts as both apro-inflammatory cytokine and an anti-inflammatory myokine. In humans,it is encoded by the 1L6 gene. IL-6's role as an anti-inflammatorycytokine is mediated through its inhibitory effects on TNF-alpha andIL-1, and activation of IL-1ra and IL-10.

RGN1538 upregulated expression of several genes which are important forthe normal differentiation and function of skin: growth factors:fibroblast growth factor 2 (FGF2) and colony stimulating factor 1(CSF1); prostaglandin transporter SLCO2A1 (including PGE and PGB);proteinase inhibitor SERPINB1.

Differential Gene Expression Induced in Fibroblasts by Compound RGN1538

The effect of Compound RGN1538L on gene expression was also analyzed incultured human adult fibroblasts by microarray and bioinformaticsanalysis. RGN1538 at concentrations 31 μM upregulated 104 genes anddownregulated 30 genes, of the total 24905 genes assessed. Atconcentration of 62 μM, RGN1518 upregulated 53 genes and downregulated76 genes. Unlike compound RGN1518, compound RGN1538 activated only fewpathways. The significant pathways impacted i.e., multiple genes in thepathway affected) by either concentration of RGN1538 are listed in Table3.

TABLE 3 Activation of pathways in fibroblasts by RGN1538 at twoconcentrations. Pathway name p-value Ribosome biogenesis in eukaryotes*1.42E−15 Ribosome* 6.76E−13 Rap1 signaling pathway 0.007 Mineralabsorption 0.009 Olfactory transduction 0.044

Importantly, of the 5 different pathways triggered by compound RGN1538only the Mineral Absorption Pathway was affected by the control,Niacinamide. Compound RGN1538, at either concentration, affected theinduction and Regulation of fibroblast growth factor production. Onlytwo genes were upregulated: Regulator of cell cycle, RGCC andProstaglandin-endoperoxide synthase 2, PTGS2.

RGN1538 upregulated 3 out of 70 genes that are involved in regulation ofendothelial cell migration: Regulator of cell cycle, RGCC;Prostaglandin-endoperoxide synthase 2, PTGS2; MIR221. Of these genes inthe biological processes of Regulation of blood vessel endothelial cellmigration, only PTGS2 is common between the control compound andRGN1538-treated fibroblasts.

Differential Gene Expression Induced in Primary Keratinocytes byCompound RGN1518

The effect of Compound RGN1518 on gene expression was also analyzed incultured human adult keratinocytes by microarray and bioinformaticsanalysis.

RGN1518 at concentrations 3.1 μM upregulated 693 genes and downregulated1294 genes, of the total 24905 genes assessed. At concentration of 1.6μM, RGN1518 upregulated 492 genes and downregulated 1196 genes.

RGN1518 downregulated a number of cell cycle genes: CDK1, PLK1, RB1,CDC25C, CDC25B, MAD2L1, CDKN2B, CCNA2, MAD1L1, TTK, ZBTB17, RBL1, CCNB1,CCNB2, BUB1, CDC20, PTTG1, BUB1B. Some of cell cycle genes wereupregulated by RGN1518: PKMYT1, MYC. The positive control, Niacinamidedownregulated only some of the genes that were also downregulated byRGN1518.

RGN1518 upregulated expression of several genes which are important forthe normal differentiation and function of skin: targets: Anti-agingtargets: fibroblast growth factor 2 (FGF2) and vascular endothelialgrowth factor A (VEGFA). Positive control, Niacinamide, upregulated FGF2to lesser extend and had no effect on VEGFA; proteinase inhibitorSERPINB1, protects from damage at inflammatory sites; CDH4 (cadherin,cell-cell adhesion); GDF15 (ligand of the TGF-beta, regulates geneexpression).

The above genes are not affected by positive control Niacinamide.

Gene expression of a number of genes involved in maintaining thestructure and activity of the Golgi apparatus was upregulated byRGN1518: COG6 (maintaining normal structure and activity of Golgiapparatus); ARFGAP3 (regulates the early secretory pathway of proteinsin Golgi apparatus); IFT20 (trafficking of proteins from the Golgi);MGAT4 (key glycosyltransferase, regulates formation of branching inGolgi). With the exception of MGAT4A, these genes were not affected bypositive control Niacinamide.

RGN1518 upregulated a number of genes involved in Metabolic Pathways: GK(key enzyme in the regulation of glycerol uptake and metabolism); FA2H(synthesis of sphingolipids); ASS1 (encoded protein catalyzes step ofthe arginine biosynthesis); ACSS2 (enzyme catalyzes activation for lipidsynthesis and energy generation); HK2 (hexokinase involved in the firststep of most glucose metabolism pathways); PHGDH (enzyme which isinvolved in the early steps of amino acid synthesis); CYP1A1 (member ofcytochrome P450 superfamily, involved in drug metabolism); CSGALNACT2(involved in elongation during chondroitin sulfate biosynthesis). Fromall above genes only two, ASS1 and PTGS2, were affected by positivecontrol Niacinamide.

A number of genes involved in Metabolic Pathways was downregulated byRGN1518: MTHFD1 (de novo purine biosyntheses); CYP2J2 (metabolism andsynthesis of cholesterol, steroids and other lipids); RRM2 (catalyzesthe formation of deoxyribonucleotides from ribonucleotides); TYMS(thymidylate synthase catalyzes the methylation of deoxyuridylate todeoxythymidylate). Of these, only TYMS was downregulated by positivecontrol.

RGN1518 upregulated several genes associated with inflammation: IL1A;IL6; cytokine receptors IL1R2 and IL1RL1, IL2RG; TSC22D3 (key role inthe anti-inflammatory response of steroids). Niacinamide downregulatedIL1A, and cytokine receptors IL1R2, but had no effect on IL1RG andIL1RL1 receptors.

RGN1518 upregulated DNAJB9 (protecting stressed cells from apoptosis)while Niacinamide downregulated expression of DNAJB9.

Effect of Compound RGN1518 on Fibroblast Gene Expression

The effect of Compound RGN1518 on gene expression in culturedfibroblasts was analyzed by microarray and bioinformatics analysis. Atotal of 24905 genes were assessed. RGN1518 at concentrations 25 μMupregulated 986 genes and downregulated 430 genes At concentration of 50RGN1518 upregulated 821 genes and downregulated 468 genes. As indicatedin Table 4, several pathways were found to be significantly impacted byboth concentrations of RGN1518.

TABLE 4 Activation of different pathways in fibroblasts treated byRGN1518 Pathway name p-value Protein processing in endoplasmic 3.66E−07reticulum Mineral absorption 4.92E−06 Apoptosis 2.27E−05 MAPK signalingpathway 3.68E−05 Transcriptional misregulation in cancer 6.83E−05

Similar pathways were induced by the control compound; therefore welooked biological processes and compared it to positive control.

Dermal fibroblasts play a critical role in wound healing. Withoutfibroblasts, the wound site cannot regenerate extracellular matrix andepidermal skin cells cannot proliferate to cover the wound site. At bothdoses, compound RGN1518 upregulated 28 genes (Table 5) and downregulated24 genes (Table 6) that are involved in wound healing.

TABLE 5 List of wound healing genes upregulated by RGN1518 infibroblasts Gene Symbol ID Log Fc p-value THBD 7056 4.118987348 0.000001IL6 3569 2.577639195 0.00000538 MIR221 407006 1.647729951 0.00000569TFPI2 7980 2.549224855 0.0000126 HMOX1 3162 1.346484873 0.0000133TNFAIP3 7128 2.328171764 0.0000148 ITGA2 3673 2.425473717 0.0000177UBASH3B 84959 1.545735901 0.0000306 ADAM17 6868 1.322521548 0.0000319ITGB3 3690 2.050790583 0.0000573 IFRD1 3475 1.071802325 0.0000848 IRF13659 1.269745256 0.00013416 PLAUR 5329 1.076502393 0.000213878 MIR199A1406976 2.14210024 0.000609993 EREG 2069 2.168964554 0.000803647 ITPR13708 1.811719476 0.000903574 PDPN 10630 1.265098302 0.001343646 MAFK7975 1.267303212 0.001984998 F2RL2 2151 1.037989039 0.002202885 SYT79066 1.079461055 0.002240755 FGFR1OP2 26127 1.212770892 0.002992132 NDNF79625 1.131823923 0.00390376 RAB27A 5873 1.228332024 0.005744187 IL2411009 1.178998478 0.009176905 HBEGF 1839 1.224660941 0.011086897 DGKE8526 1.432277168 0.017099125 PLET1 349633 1.411842526 0.018677613 MERTK10461 1.107372666 0.026124331

Upregulation of genes useful in the wound healing process indicates thatthe compound could be applied topically to skin wounds to improve thespeed and efficiency of the healing process in different types ofwounds, such as cuts, burns, skin ulcers, sores, diabetic wounds andwounds occurring in elderly people, which are both major problems.

For example, HMOX1 (heme oxygenase (decycling) 1) is a human gene thatencodes for the enzyme heme oxygenase 1 (EC 1.14.99.3). Heme oxygenasemediates the first step of heme catabolism, it cleaves heme to formbiliverdin. The ability of oxygenase 1 to catabolize free heme andproduce carbon monoxide (CO) gives its anti-inflammatory properties byup-regulation of interleukin 10 (IL-10) and interleukin 1 receptorantagonist (IL-1RA) expression.

IL-6 has a direct, crucial role in proliferation and remodeling phasesof wound healing by promoting collagen deposition and angiogenesis.Following damage of the epidermis, primary inflammatory cytokines likeTNFα and IL-1 are released and in turn, induce expression of IL-6.Primary inflammatory cytokines mediate inflammatory cell accumulation intissues, resulting in further damage. IL-6 counters this by inhibitingthe expression of primary inflammatory cytokines. IL-6 itself mediatesskin healing, and may promote the influx or differentiation ofanti-inflammatory macrophage populations that further promote repair.

TABLE 6 List of wound healing genes downregulated by RG1518 infibroblasts. Gene Symbol ID Log Fc p-value HIST1H3G 8355 −2.3393036380.00000243 MYLK 4638 −1.620014296 0.00000314 WNT5A 7474 −1.7322161690.0000115 THBS1 7057 −1.28731505 0.0000126 LBH 81606 −1.5240011480.0000151 PLPP3 8613 −1.229647888 0.00002 TPM1 7168 −1.2094400730.0000408 TGFBR2 7048 −1.067098852 0.0000522 NOV 4856 −1.5243033310.0000541 AJUBA 84962 −1.145313108 0.0000647 TLN1 7094 −1.1295938270.0000667 SMAD3 4088 −1.102006837 0.0000719 F3 2152 −1.0392106220.0000783 PDGFD 80310 −1.782304634 0.0000783 EDN1 1906 −1.4043119670.0000916 ACTB 60 −1.055146506 0.0000953 HIST2H3A 333932 −1.2849382370.000100719 GSN 2934 −1.040857201 0.00017024 CARMIL1 55604 −1.1773824430.00025843 FGF10 2255 −1.3129405 0.000304636 TMEFF2 23671 −1.5259957590.000356268 GATA6 2627 −1.080645213 0.000696771 TRPC6 7225 −2.4443641670.002443487

Importantly, the upregulation of genes underlying the wound healingprocess by the positive control Niacinamide is the number of stimulatedbiological processes is significantly less pronounced than with the testcompounds. For example, the gene profile of compound RGN1518 pointed tothe activation of vascular wound healing and spreading of epidermalcells as well as vasculature development while Niacinamide showed noeffect on these biological processes. Among genes whose upregulation isassociated with vasculature development are the following: HistoneCluster 1 H3 Family Member G, HIST1H3G; Myosin Light Chain Kinase, MYLK;Transient Receptor Potential Cation Channel Subfamily C Member 6, TRPC6;Endothelin 1, EDN1; Histone Cluster 1 H3 Family Member G, HIST1H3G.

Different biological processes such as hair cycle, hair folliclemorphogenesis and development are also affected by both concentrationsof RGN1518 in hair cycle process. Importantly, only 2 out of 6upregulated genes are common in RGN1518 and positive control: GORAB;LRIG1. Other 4 genes; PER1; PTGS2; ARNTL; SNAI1. Other 4 genes areupregulated only by positive control: GAL; INHBA; TGFB2; FZD3.

Both concentrations of RGN1518, and positive control affected biologicalprocess underlying Muscle Structure Development and Muscle CellProliferation. RGN1518 upregulated gene expression of common skintargets: Epidermal growth factor-related protein, function as adhesionmolecule, CRELD1; Nerve growth factor, NGF; Glutaredoxin, highlycontributes to the antioxidant defense system, GLRX2; Protein involvedin chondroitin sulfate synthesis, CSGALNACT2; Vascular endothelialgrowth factor A, VEGFA; Receptor for collagens, adhesion of cells to theextracellular matrix, ITGA2; Peroxisome proliferator activated receptorgamma, PPARG; Epidermal growth factor receptor, role in survival,proliferation, migration, EPGN

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Publications cited herein andthe materials for which they are cited are specifically incorporated byreference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. A cosmetic composition comprising: a) a quinone having thestructural formula:

or mixtures thereof, in amounts ranging from 0.001% to 50% by weight ofthe composition; b) a cosmetic functioning component selected from thegroup consisting of sunscreens, surfactants, sunless tanning agents,desquamation agents, antiperspirants, colorants, preservatives andmixtures thereof in amounts ranging from 0.0001% to 50% by weight of thecomposition; and c) a cosmetically acceptable carrier; wherein R1, R2,R3, R4, R5, R6, R7, and R8 are independently hydrogen, unsubstitutedC1-C10 alkyl, substituted C1-C10 alkyl, unsubstituted C2-C10 alkenyl,substituted C2-C10 alkenyl, hydroxyl, thiol, halogen, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy,aroxy, substituted aroxy, alkylthio, substituted alkylthio, arylthio,substituted arylthio, carbonyl, substituted carbonyl, carboxyl,substituted carboxyl, amino, substituted amino, amido, substitutedamido, polyaryl, substituted polyaryl, C3-C20 cyclic, substituted C3-C20cyclic, heterocyclic, substituted heterocyclic; and wherein R9, R10,R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and R23 areindependently hydrogen, unsubstituted C1-C10 alkyl, substituted C1-C10alkyl, hydroxyl, ═O, substituted C1-C10 carbonyl, or unsubstitutedC1-C10 carbonyl, thiol, halogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkoxy, substituted alkoxy, aroxy, substitutedaroxy, alkylthio, substituted alkylthio, arylthio, substituted arylthio,carboxyl, substituted carboxyl, amino, substituted amino, amido,substituted amido, polyaryl, substituted polyaryl, C3-C20 cyclic,substituted C3-C20 cyclic, heterocyclic, substituted heterocyclic. 2.The cosmetic composition of claim 1, wherein R1, R2, R3, R4, R5, R6, R7,and R8 are independently hydrogen, unsubstituted C1-C10 alkyl,substituted C1-C10 alkyl, unsubstituted C2-C10 alkenyl, or substitutedC2-C10 alkenyl; and wherein R9, R10, R11, R12, R13, R14, R15, R16, R17,R18, R19, R20, R21, R22, and R23 are independently hydrogen,unsubstituted C1-C10 alkyl, substituted C1-C10 alkyl, hydroxyl, ═O,substituted C1-C10 carbonyl, or unsubstituted C1-C10 carbonyl.
 3. Thecosmetic composition of claim 1, wherein for Formula I, R2 and R4 areeach hydrogen.
 4. The cosmetic composition of claim 3, wherein forFormula I, R1 and R3 are independently unsubstituted C1-C10 alkyl, orsubstituted C1-C10 alkyl.
 5. The cosmetic composition of claim 4,wherein for Formula I, R1 is substituted C1-C5 alkyl; R3 is methyl, andR2 and R4 are each hydrogen.
 6. The cosmetic composition of claim 5,wherein Formula I is


7. The cosmetic composition of claim 1, wherein for Formula II, R5, R6,R7, and R8 are independently hydrogen, C1-C10 alkyl, or substitutedC1-C10 alkyl.
 8. The cosmetic composition of claim 7, wherein forFormula II, R5, R6, R7, and R8 are hydrogen.
 9. The cosmetic compositionof claim 8, wherein for Formula II, R1 and R2 are independentlyunsubstituted C2-C10 alkenyl, substituted C2-C10 alkenyl, C1-C10 alkyl,substituted C1-C10 alkyl, or hydroxyl.
 10. The cosmetic composition ofclaim 9, wherein for Formula II, R1 and R2 are independentlyunsubstituted C2-C10 alkenyl, substituted C2-C10 alkenyl, or hydroxyl.11. The cosmetic composition of claim 10, wherein for Formula II, R1 issubstituted C2-C10 alkenyl, and R2 is hydroxyl.
 12. The cosmeticcomposition of claim 11, wherein Formula II is


13. The cosmetic composition of claim 1, wherein for Formula III, R9 issubstituted C1-C10 carbonyl.
 14. The cosmetic composition of claim 13,wherein for Formula III, R10 is hydroxyl.
 15. The cosmetic compositionof claim 14, wherein for Formula III, X is carbon (C) or CH, Y is carbon(C), Z is hydroxyl, the dashed line between X and Y is a bond, and thedashed line between Y and Z is absent.
 16. The cosmetic composition ofclaim 15, wherein for Formula III, R17 is hydroxyl.
 17. The cosmeticcomposition of claim 16, wherein for Formula III, R11, R12, R13, R14,R15, R16, R18, R19, R20, R21, R22, and R23 are independently hydrogen,substituted C1-C10 alkyl, or unsubstituted C1-C10 alkyl.
 18. Thecosmetic composition of claim 17, wherein for Formula III, R11, R12,R13, R14, R20, R21, R22, and R23 are unsubstituted C1-C10 alkyl; andR15, R16, R18, and R19 are independently hydrogen or substituted C1-C10alkyl.
 19. The cosmetic composition of claim 18, wherein for FormulaIII, R11, R12, R13, R14, R20, R21, R22, and R23 are unsubstituted C1-C5alkyl; and R15 and R18 are hydrogen, R16 and R19 are substituted C1-C5alkyl.
 20. The cosmetic composition of claim 19, wherein for FormulaIII, R11, R12, R13, R14, R20, R21, R22, and R23 are methyl; R15 and R18are hydrogen.
 21. The cosmetic composition of claim 20, wherein forFormula III, R16 and R19 are isopropyl.
 22. The cosmetic composition ofclaim 11, wherein Formula III is


23. The cosmetic composition of 1, wherein UV irradiated samples of thequinone or cosmetic composition formulated with the quinone exhibit, intesting against a CUL4A bio target, a reduction in DNA damage relativeto a UV irradiated control of at least 10%, as measured by % cyclobutanepyrimidine dimer (CPD) formed in a test cell.
 24. The cosmeticcomposition according to claim 1, wherein the sunscreens are selectedfrom the group consisting of 2-ethylhexyl p-methoxycinnamate,4,4′-t-butyl methoxydibenzoylmethane, octylsalicylate,tetraphthalylidene dicamphor sulfonic acid, benzophenone-3, microfinetitanium dioxide, micro zinc oxide and mixtures thereof.
 25. Thecosmetic composition according to claim 1, wherein the surfactants areselected from the group selected consisting of anionic, nonionic,cationic, and amphoteric type.
 26. The cosmetic composition according toclaim 1, wherein the sunless tanning agents are dihydroxy acetone. 27.The cosmetic composition according to claim 1, wherein the desquamationagents are selected from the group consisting of glycolic acid, lacticacid, salicylic acid, retinoic acid, retinol and mixtures thereof, andincluding salt forms thereof.
 28. The cosmetic composition according toclaim 1, wherein the antiperspirants are selected from the groupconsisting of metal salts of aluminum, zinc, zirconium and zirconiumaluminum mixtures of sulfates, chlorides, chlorohydroxides,tetrachlorohydrex glycinates, alums, formates, lactates, benzylsulfonates, succinates, and phenol sulfonates.
 29. The cosmeticcomposition according to claim 1, wherein the colorants are selectedfrom pigments and dyes.
 30. The cosmetic composition according to claim1, wherein the preservatives are selected from the group consisting ofmethylchloroisothiazolinone and methylisothiazolinone combinations,phenoxyethanol, methyl paraben, propyl paraben, imidazolidinyl urea,sodium dehydroacetate and benzyl alcohol.
 31. A method for treating asite in need thereof in mammals selected from the group consisting ofagin skin, dermatitis and a wound site, comprising topically applying tothe skin or hair of the mammals a cosmetic composition comprising aquinone having the structural formula:

or mixtures thereof in amounts ranging from 0.001% to 10% by weight ofthe cosmetic composition, wherein R1, R2, R3, R4, R5, R6, R7, and R8 areindependently hydrogen, unsubstituted C1-C10 alkyl, substituted C1-C10alkyl, unsubstituted C2-C10 alkenyl, substituted C2-C10 alkenyl,hydroxyl, thiol, halogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkoxy, substituted alkoxy, aroxy, substitutedaroxy, alkylthio, substituted alkylthio, arylthio, substituted arylthio,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, polyaryl, substitutedpolyaryl, C3-C20 cyclic, substituted C3-C20 cyclic, heterocyclic,substituted heterocyclic; and wherein R9, R10, R11, R12, R13, R14, R15,R16, R17, R18, R19, R20, R21, R22, and R23 are independently hydrogen,unsubstituted C1-C10 alkyl, substituted C1-C10 alkyl, hydroxyl, ═O,substituted C1-C10 carbonyl, or unsubstituted C1-C10 carbonyl, thiol,halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,alkoxy, substituted alkoxy, aroxy, substituted aroxy, alkylthio,substituted alkylthio, arylthio, substituted arylthio, carboxyl,substituted carboxyl, amino, substituted amino, amido, substitutedamido, polyaryl, substituted polyaryl, C3-C20 cyclic, substituted C3-C20cyclic, heterocyclic, substituted heterocyclic, wherein the compositionis effective to: (a) inhibit cullin 4A (CUL4A) ubiquitin ligase, (b)upregulate expression of one or more genes selected from the groupconsisting of inteleukin-6 (IL-6), fibroblast growth factor (FGF), GPHR,ADAM17 and VEGF; (c) down regulate expression of Smad3 or (d)combinations thereof.
 32. The method according to claim 31 wherein theskin shows signs of ageing selected from the group consisting of finelines and wrinkles; lack of skin firmness; reduction of skinluminescence; lack of skin smoothness; lack of skin elasticity;formation of age spots; blotching; sallowness; uneven pigmentation;spider veins; thinning and loss of hair; lack of hair lustre or shine;and hair with split ends.
 33. A method of enhancing DNA repair, themethod comprising contacting DNA with a composition comprising a quinonehaving the structural formula:

or mixtures thereof, wherein the quinone is present in amounts rangingfrom 0.001% to 50% by weight of the composition; wherein R1, R2, R3, R4,R5, R6, R7, and R8 are independently hydrogen, unsubstituted C1-C10alkyl, substituted C1-C10 alkyl, unsubstituted C2-C10 alkenyl,substituted C2-C10 alkenyl, hydroxyl, thiol, halogen, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy,aroxy, substituted aroxy, alkylthio, substituted alkylthio, arylthio,substituted arylthio, carbonyl, substituted carbonyl, carboxyl,substituted carboxyl, amino, substituted amino, amido, substitutedamido, polyaryl, substituted polyaryl, C3-C20 cyclic, substituted C3-C20cyclic, heterocyclic, substituted heterocyclic; and wherein R9, R10,R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and R23 areindependently hydrogen, unsubstituted C1-C10 alkyl, substituted C1-C10alkyl, hydroxyl, ═O, substituted C1-C10 carbonyl, or unsubstitutedC1-C10 carbonyl, thiol, halogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkoxy, substituted alkoxy, aroxy, substitutedaroxy, alkylthio, substituted alkylthio, arylthio, substituted arylthio,carboxyl, substituted carboxyl, amino, substituted amino, amido,substituted amido, polyaryl, substituted polyaryl, C3-C20 cyclic,substituted C3-C20 cyclic, heterocyclic, substituted heterocyclic. 34.The method of claim 31, wherein site selected from the group consistingof a cut, burn, skin ulcer, sore, dermatitis and diabetic ulcer.
 35. Themethod of claim 31 wherein the composition comprises


36. The method of claim 31 wherein myrtucummolone c is present betweena, 40%:60% and a 60% to 40% mixture the diastereomers.